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Ataxia telangiectasia (AT) is a rare neurodegenerative disorder caused by mutations in the ATM gene and is characterized by progressive cerebellar degeneration. Increasing evidence suggests that somatic mutations accumulating in individual neurons may contribute to selective neuronal vulnerability, yet the rate, spectrum, and functional consequences of these mutations in human brain tissue remain poorly understood. This project proposes to apply single cell genomic approaches to quantify somatic mutation rates in cerebellar neurons from individuals with AT compared to neurotypical controls. By leveraging high resolution single cell sequencing and computational analysis, the study aims to identify molecular mechanisms driving mutagenesis, determine how these mutations affect neuronal function, and assess their contribution to neurodegeneration. Results from this work will provide critical insights into how genomic instability impacts neural health and may reveal novel pathways relevant to neurodegenerative disease pathogenesis.

Opioid Use Disorder (OUD) is an ever-increasing public health concern. Despite available treatments, most patients relapse within the first few months. Therefore, there is a substantial need to understand the etiology of OUD and what mechanisms lead to increased opioid use and relapse. Notably, many patients with OUD have reported severe and persistent disruptions to sleep and circadian rhythms. Indeed, long-term opioid use is associated with increased sleep and circadian rhythm disruption, as well as intense cravings and negative affective states leading to vulnerability to relapse. Importantly, the Logan lab has shown that subregions of the striatum, specifically the nucleus accumbens (NAc), display altered molecular rhythms in OUD. Furthermore, preliminary data from the lab suggests that immune signaling in the NAc is altered due to OUD. Microglia, the primary innate immune cells in the central nervous system, have recently been implicated in OUD. Interestingly, microglia exhibit specific molecular rhythms that are dysregulated in OUD, suggesting a potential role for these cells in OUD-related sleep disruption. However, the role of microglial molecular rhythms in the NAc in OUD has yet to been fully elucidated. Thus, this proposal seeks to investigate the molecular rhythms of microglia in the NAc in OUD and how these mechanisms affect opioid-related behaviors. In the aims of this, I will use snRNAseq to characterize circadian rhythms in NAc microglia from human OUD samples and fentanyl-administering mice of both sexes. Additionally, I will disrupt molecular rhythms in microglia using cell type-specific conditional knockout (cKO) of Bmal1 in mice, a master regulator of circadian rhythm, to determine whether inflammatory gene expression and chromatin accessibility is altered. Furthermore, I will examine whether Bmal1 cKO mice display altered drug-taking behavior using fentanyl self-administration. Results from these studies will provide novel insights into microglial molecular rhythms across species and how they contribute to OUD-related behaviors.

Alpha-1 antitrypsin disease (AATD) is caused by mutations in the SERPINA1 gene, which encodes AAT protein. AAT is produced in liver and delivered via serum to lungs, where it inhibits neutrophil elastase. The most common AATD allele—called PI*Z—is a G-to-A mutation that produces a dysfunctional misfolded protein, Z-AAT, that aggregates in hepatocytes, which can cause liver disease; reduced serum AAT causes pulmonary emphysema. Currently, the only approved therapy for AATD emphysema is costly, weekly infusions of purified AAT for life. CRISPR/Cas9-mediated homology directed repair (HDR) can correct PI*Z in the liver and partially restore serum AAT levels in an AATD mouse model. Yet, HDR is limited by the need to deliver a DNA repair template, its inefficiency in non- and slow-dividing cells, and its generation of genotoxic double-strand breaks. By contrast, CRISPR-mediated adenine base editors (ABEs) support precise editing without requiring a DNA donor or double-strand breaks. ABE consists of adenine deaminase (TadA) conjugated to Cas9 nickase. When directed by a guide RNA to a specific sequence, ABE deaminates adenine in a defined editing window. The resulting inosine is read as guanosine, thereby converting A to G. Thus, ABE is a good candidate for PI*Z correction. Preliminary evidence shows that viral delivery of a compact ABE, utilizing an evolved Cas9 nickase derived from Neisseria meningitidis (eNme2-C ABE), to PI*Z transgenic mice leads to efficient editing of PI*Z in hepatocytes to significantly reduce liver disease. Yet, eNme2-C ABE deaminates not only the target adenine but also “bystander” adenines in the designated editing window, leading to mutations of unknown consequence. Moreover, the level of base editing needed to rescue lung disease is undetermined. This project seeks to optimize ABE precision for PI*Z correction and assess the therapeutic potential of ABE in treating emphysema in a mouse model of AATD. Aim 1 will characterize ABE off-target and bystander edits for PI*Z correction. TadA variants with distinct editing windows have been developed, including ABE8e and ABE9e. eNme2-C ABE8e and ABE9e edit both the target adenine and bystander adenines at the PI*Z target locus in PI*Z reporter cells. Off-target editing events by each variant will be detected and validated in PI*Z reporter cells and liver cells by deep sequencing and RNA sequencing. Bystander alleles generated by each variant will be identified, then in vitro approaches will be used to analyze the secretion and activity of each AAT bystander mutant. Aim 2 will characterize ABE-mediated PI*Z correction and lung function in AAT-null PI*Z mice, which exhibit both lung and liver disease. eNme-2 ABE will be delivered by AAV to AAT-null PI*Z mice, and pulmonary mechanics will be measured over 10 weeks. At endpoint, serum, liver, and lung tissue will be collected to measure serum AAT level, PI*Z correction and hepatocyte AAT aggregates, and alveolar morphometry. This proposal will inform the development of base editing strategies to treat AATD and provide the fellow with training in therapeutic genome editing and genetic disease biology.

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Scot Wolfe, PhD, is developing a CRISPR-Cas9 strategy to selectively destroy cancer cells driven by focal gene amplification.

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Pancreatic cancer is highly metastatic, and patients are often not diagnosed until metastases have already formed, with the vast majority (>75%) presenting with oligometastatic disease. Current genetically engineered mouse models of pancreatic cancer are metastatic in 30-40% of animals and harbor only small focal metastases, complicating the study of metastatic drivers in mice. Preliminary experiments identified Calcium/calmodulin- dependent protein kinase II beta, Camk2b, as a gene whose loss enhances tumor metastasis and creates a highly immunosuppressive tumor microenvironment (TME). Genetically engineered mice with tumor cell-specific Camk2b knockout form metastases in 80% of animals and present with >25 metastatic lesions per mouse. Metastatic burden is so profound in this model that the animals succumb to disease twice as fast as control tumor bearing mice. Preliminary results, show that deletion of Camk2b results in tumors that are more metastatic and express higher levels of Lysyl Oxidase (Lox). Aim 1 will focus on exploring tumor cell intrinsic mechanisms through which Camk2b-deletion promotes tumor cell metastasis. The metastatic cascade typically begins by the modulation of tumor cell epithelial identity through programs such as epithelial-to-mesenchymal (EMT). Thus, Subaim 1.1 will investigate the effect of Camk2b loss on tumor cell epithelial cell identity using isogenic cell lines, genetically engineered mouse model, and patient-derived organoid systems. Subaim 1.2 will investigate the functional contribution of LOX on metastatic competency and the ability of LOX-targeting to block metastatic outgrowth. Preliminary experiments indicate that deletion of Camk2b in tumor cells shifts the immune milieu towards a pro- tumor state that is more permissive to tumor metastasis. In this regard, Camk2b-null tumor cells alter their local microenvironment and confer an immune desert phenotype that may facilitate tumor growth and metastasis. To explore mechanisms of this immunosuppressive phenotype, Aim 2 will test the contribution of the immunosuppressive microenvironment in Camk2b-null tumors on metastasis. Subaim 2.1 will selectively deplete macrophages in Camk2b-deletion tumors and evaluate the impact on the metastatic niche and gross tumor cell metastasis. Subaim 2.2 will investigate the contribution of Tbc1d9, a calcium-responsive gene activated in Camk2b deleted tumor cells, to suppression of the NK and T cell response. Collectively, our work will demonstrate that Camk2b is a metastasis suppressing gene whose loss activates pro- metastatic signaling networks. Our functional and mechanistic work will define targetable downstream signaling nodes, within tumor cells and in the microenvironment, to block immunosuppression and metastatic outgrowth.

Center for Integrated Primary Care, UMass Medical School, Degree of Behavioral Health Integration and Patient Outcomes

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Reflections from My Measurement-Based Care Teeter Totter of Ambivalence By: Amber Cahill, PsyD

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Project Summary Mutations in genes encoding proteins that are essential for cell processes such as DNA replication can lead to cellular dysfunction and disease. Protein defects can perturb these cell processes by removing or surpassing cell cycle checkpoints, leading to errant growth and proliferation of cells, defining characteristics of cancer. As such, it is essential to investigate Proliferating Cell Nuclear Antigen (PCNA), the central player that coordinates DNA replication, DNA repair, and cell-cycle regulation. PCNA, also known as the sliding clamp, is a homotrimeric ring that slides along DNA to facilitate interactions of over 100 known proteins, many involved in cancer development and other important cellular processes. The sliding clamp is conserved across all life forms, providing insight into the evolution of DNA replication and cell-cycle machinery. Thus, PCNA is an ideal target to investigate mutational effects on protein function and the long-term impacts on the cell. In Aim 1, we will address an interesting paradox related to PCNA. Point mutations in PCNA that result in subtle biochemical effects cause severe disruption of organism fitness, suggesting that PCNA is especially sensitive to mutations. Conversely, PCNA genes across evolution are widely varying in sequence suggesting that PCNA is actually accepting of mutations. To investigate this contradiction, we will perform a mutational scan of all potential point mutations in the yeast PCNA protein. These mutants will then be exposed to DNA-damaging agents to assess the effects of the PCNA mutants on various PCNA functions. I predict that a mutational screen of PCNA will show mutational effects on cell viability and DNA damage response based on residue location in PCNA providing insight into the acceptability of point mutations in PCNA. This data will also provide insights into potential disease mutations that could impact human PCNA. The Kelch lab has previously investigated two disease-associated germline mutations in PCNA. These mutations lead to PCNA-associated DNA repair disorder (PARD), characterized by UV sensitivity, neurodegeneration, premature aging, and, most notably, the development of skin cancer. In Aim 2, we will investigate how patient-associated mutations in PCNA affect biochemical and cellular function. I selected variants based on association with cancer or PARD. I will establish mutant human retinal pigment epithelial (RPE1) cell lines using CRISPR/Cas9 techniques. Once these cell lines are established, I will assess the cellular impacts by using flow cytometry and DNA-damage assays. I will compare these results with tests of the biochemical functions using isothermal titration calorimetry and thermal shift assays. I predict that the mutations will exhibit defects in thermostability, cell regulation, and DNA repair. The impact of this study is two- fold. First, the study will enhance our understanding of how PCNA function and evolution are intertwined. Second, the study will investigate select human PCNA mutants that can inform cancer diagnosis and provide a framework for investigating other proteins.

Amyotrophic lateral sclerosis (ALS) is a devastating degenerative motor neuron disease that is largely untreatable and leads to death within 5 years of diagnosis. ~10% of ALS cases are familial and caused by mutations in various ALS genes. Ultimately, the ideal treatment for genetic diseases such as ALS is somatic gene correction. Recently, advances in CRISPR/Cas systems have shown considerable promise for precise editing of disease loci using base and prime editing systems delivered by AAV. The second-most prevalent cause of familial ALS are mutations in the SOD1 gene. These mutations confer multiple toxic properties onto the protein. This project proposes to develop treatment to achieve somatic gene correction for common missense mutations in SOD1. The aims of this proposal are: (1) To develop AAV-mediated base editing gene correction strategies for the SOD1 A5V mutation in vitro. We will create next-generation base editors with a compact size, increased efficiency, and greater control over bystander editing. (2) To develop AAV-mediated prime editing gene correction strategies for the SOD1 A5V and G94A mutations in vitro. Different prime editor systems will be tested for optimal editing efficiencies and low off-target editing. (3) In in vivo studies, examine and optimize AAV- mediated base and prime editing gene correction strategies for the A5V and G94A mutations in A5V and SOD1G93A mouse models. Mice will receive AAV-mediated base and prime editors through an intracerebroventricular injection. Base and prime editor strategies will first be screened in mutation carrying HEK293T cells and then optimized in patient fibroblasts and mouse models. The effects of gene correction on gain- and loss-of-function molecular and motor phenotypes will next be evaluated. The fundamental hypothesis driving this proposal is that AAV-mediated somatic gene correction strategies, using base editing or prime editing to target the SOD1 mutations A5V and G94A, will decrease toxic GOF pathology and increase WT SOD1 protein levels in vivo, resulting in a balanced treatment for SOD1-ALS and a rescue of motor phenotype. In addition, with mentorship from experts in ALS and gene editing and the wealth of resources available at UMASS Chan, these studies will provide extensive training in gene editing for CNS diseases and project development that will be an essential foundation for a future career as an independent researcher developing gene therapies for a range of genetic CNS diseases.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a cytosolic double- stranded DNA (dsDNA) sensing pathway critical for regulating immune homeostasis. A series of gain-of-function (GOF) mutations result in constitutive activation of STING, causing an autoinflammatory disease called STING- Associated Vasculopathy with Onset in Infancy (SAVI). SAVI patients succumb to treatment resistant inflammatory lung disease and respiratory failure. There is little known about the mechanisms by which inflammation occurs. To address the urgent need to develop safe and effective therapies, we have developed a murine model for the most common STING gain-of-function mutation, STINGV154M/WT (VM). These mice recapitulate the lung inflammation exhibited by human SAVI patients. To identify the specific cell types involved in causing lung inflammation, we developed a novel VM conditional knock-in (CKI), allowing specific targeting of the VM mutation to different cell types. We demonstrated that endothelial cell (EC) STING GOF is sufficient in driving bronchus-associated lymphoid tissue (BALT) formation. However, the mechanism of action remains to be elucidated. Moreover, we have previously described SAVI lung disease as independent of type I interferon (IFN) and IRF3, signaling proteins downstream of STING activation. STING activation leads to downstream signaling of other pathways including NF-κB and autophagy. The signaling mechanism causing lung inflammation is also unknown. Additionally, STING GOF in ECs was insufficient to cause the extent of lung inflammation seen in VM mice, suggesting STING GOF in cells other than ECs is required for lung disease. Upon ubiquitous VM expression, we find evidence of fibroblast activation in the lung tissue. Fibroblastic reticular cells (FRCs) are a subset of fibroblasts that define the function and structure of lymphoid organs such as BALT. In addition to ECs, STING is highly expressed in FRCs, yet the role of STING in FRCs and contributions to lung disease is unknown. Thus, we hypothesize that coordinated interactions between ECs and FRCs exacerbate SAVI lung autoinflammation, which is dependent on NF-κB activation. In this proposal, Aim 1 will investigate how STING GOF mutation in ECs initiates immune cell recruitment. Aim 2 will determine the synergistic effects of STING GOF mutation in ECs and FRCs on lung autoinflammation. We propose to utilize in vivo, ex vivo, and in vitro techniques to test our hypothesis. The studies proposed in this application will provide critical insights that will enable us to design the best therapies. Furthermore, these studies will provide an opportunity to study the impact of STING activation on stromal cell types, an area of research that requires further exploration. Our findings will discern the role of ECs and FRCs in VM lung autoinflammation and will broadly provide insight into stromal cell-driven mechanisms of other lung disorders.

Tuberous sclerosis complex (TSC) is caused by Tsc1 or Tsc2 mutations and can affect several organs, including the kidneys, leading to benign tumors or cyst formation. Impaired TSC1/2 protein function promotes hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1), an important cellular nutrient sensor that controls cell growth and proliferation. However, a much deeper mechanistic understanding of mTORC1 regulation and function in kidney cells is required. The mTORC1 kinase complex is activated by the essential amino acid sensors called Rag-GTPases. There are four Rag GTPases isoforms (RagA, RagB, RagC, and RagD), which localize to lysosomes and function in a heterodimeric complex where RagA/RagB binds to RagC/RagD. The Rag-GTPase complex positively regulates mTORC1 by recruiting it to the lysosomal surface in the presence of amino acids, where mTORC1 is subsequently stimulated by another small GTPase called Rheb. The activated mTORC1 complex signals to several substrates that collectively regulate cell metabolism, growth, and proliferation, key factors for developing kidney cysts. Importantly, all current models indicate that RagA/B loss will inhibit mTORC1 signaling by preventing its localization to the lysosome. Unexpectedly, we discovered that deleting RagA and RagB in kidney tubular epithelial cells causes a striking and progressive cystic phenotype resembling TSC. Moreover, RagA/B deletion in the kidney is associated with increased, rather than decreased mTORC1 signaling, as in TSC. This phenotype is not observed when we delete the mTORC1 subunit Raptor in the kidney epithelium. Thus, we hypothesize that RagA/B loss triggers kidney cystogenesis via a non-canonical Rag-GTPase pathway, involving TFEB regulation and possible cellular crosstalk for mTORC1 hyperactivation, which can be a common mechanism of TSC cyst formation. Since aberrant mTORC1 activation is a hallmark of TSC and other kidney cystic diseases, resolving this unexpected mechanism and the Rag-GTPases role in kidney cyst development may have important translational implications for improving upon current mTOR-based therapeutic strategies for the management of TSC and other kidney cystic diseases. In this proposal, I aim to (1) identify the cellular origin and metabolic traits underlying RagA/B deletion-induced kidney cystogenesis, and (2) determine the mechanism linking RagA/B loss and mTORC1 activation, TFEB regulation, and the similarities to the pathophysiology of TSC.

Mitochondria support multifaceted metabolic reactions in mammalian cells1. The vast majority of these metabolic pathways require the electron transport chain (ETC), a series of reactions in which ubiquinone (UQ) carries electrons to oxygen (O2) as the terminal electron acceptor (TEA). Recent studies have refuted this textbook model and have shown fumarate as a TEA2 through two mechanisms. First, under hypoxia, the reduced electron carrier ubiquinol accumulates driving complex II backwards to deliver electrons to fumarate. Second, in normoxic conditions, a novel mammalian metabolite rhodoquinone (RQ) can deliver electrons to fumarate3. Thus, the mammalian ETC is highly flexible and whether other electron acceptors beyond fumarate and O2 can be used has yet to be studied. The thermodynamic favorability of all reduction and oxidation (redox) reactions in the ETC are dictated by the Nernst equation. Electrons favorably transfer from metabolites with low to high reduction potential4. Thus, as RQ has a lower reduction potential than UQ, it can theoretically deliver electrons to other electron acceptors such as sulfites. Moreover, upon hypoxia exposure, UQH2 can build up enough to enable sulfites reduction as well. Oxidized sulfur-based molecules are known to act as TEA in certain sulfate-reducing prokaryotes5. The same molecules are known to interact with the mammalian ETC via enzymes sulfite oxidase (SUOX) and sulfide quinone oxidoreductase (SQOR) with cytochrome c and UQ, respectively. Importantly, SUOX functions in the cysteine catabolic pathway to oxidize sulfite (SO3-2) into sulfate (SO4-2), subsequently transferring electrons to cytochrome c6. Similarly, SQOR oxidizes hydrogen sulfide (H2S) to glutathione persulfide (S2O3-2) by transferring electrons to UQ6. Although these electron donor mechanisms (Fig.1) are well established, the reversibility of these reactions, enabling reduction of sulfate and glutathione persulfide as electron acceptors, have never been examined in mammals. We hypothesize that sulfate via SUOX and glutathione persulfide via SQOR can serve as TEA for UQ-dependent ETC circuits in hypoxic (low oxygen) environments, and RQ-dependent ETC circuits at any oxygen tension (Fig. 2). The proposed research will test the propensity for mammalian cells using the UQ- and RQ-directed ETC circuits to employ oxidized sulfur species as TEA. We will leverage directing UQ vs RQ circuits in vitro to measure reversibility of SUOX and SQOR activities in varying oxygen availabilities (Aim 1) and an established conditional mouse model to examine the tissue specificity of these enzymes and circuits (Aim 2). This work will add to the growing body of literature on novel mechanisms of flexibility in the mammalian ETC and will provide meaningful insights to mitochondrial function. [1]Monzel, Nat Met 2023 [2]Spinelli, Science 2021 [3]Valeros, Cell 2025 [4]Alberts, Mol Bio of the Cell., 2002 [5]Muyzer, Nat Rev Microbiol 2008 [6]Kohl, Br J Pharmacol 2019

Cardiovascular disease is the leading cause of death in the United States. Despite decades of research, it is unclear how the RNase A family nuclease angiogenin stimulates blood vessel formation, and why angiogenin dysfunction is associated with heart failure and poor cardiovascular health. Recent work revealed that angiogenin’s nuclease activity, which is required for its angiogenic function, is stimulated by binding to the ribosome, but it remains unclear whether angiogenin’s ribosome-dependent mechanism is involved in angiogenesis. A bacterial nuclease named ribocin with a strikingly angiogenin-like structure and ribosome- dependent activity holds similar potential for understanding lung health. Nearly all Cystic Fibrosis patients experience Pseudomonas aeruginosa bacterial pneumonia and subsequently suffer from lung tissue inflammation and lasting damage long after the infection has cleared. Ribocin encoded by P. aeruginosa damages human ribosomes specifically at central helix 69 of the 28S rRNA and inhibits translation. We hypothesize that like other ribosome-inactivating proteins, ribocin induces a ribotoxic stress response that causes inflammation and cell death in human lung tissues. To inform future therapeutic studies aimed at treating cardiovascular disease and post-infection pulmonary damage, the mechanisms of translation control by these RNase A-family nucleases must be elucidated in the context of their cellular functions. The goal of this project is to determine the structural basis of translation control by angiogenin during angiogenesis and determine the impact of translation control by ribocin on ribotoxic stress response and cell death. With guidance from the sponsor, an expert in biochemical and structural basis of translation, and collaborators, who are experts in the RNA developmental biology and cryo-EM method development, the trainee will apply cutting edge methods for in-cell cryogenic electron microscopy (cryo-EM) complemented by cell assay and biochemical approaches to visualize structural changes to actively translating ribosomes during angiogenin- stimulated vascularization and ribocin-mediated tissue damage. Aim 1 will determine the contribution of angiogenin’s ribosome-specific activity on tube formation (angiogenesis) in human umbilical vascular endothelial cells (HUVEC). Aim 2 will elucidate the structural mechanism of translation inhibition by ribocin and investigate the impact of selective ribosome damage by ribocin on ribotoxic stress response in human lung cells (IB3). The results of this study will reveal details of mechanisms underlying fundamental cardiovascular function and novel components of pulmonary disfunction, necessary for future work in developing therapeutics for cardiovascular and lung disease.

As we age, cells accumulate damage, become less efficient at converting energy and produce more toxic byproducts leading to an overall decline of the human body. This decline is linked to mitochondria, the cells energy supplier. Normally mitochondria rely on oxygen to provide energy, which comes at the cost of producing toxic molecules in the process. However, it was recently found that a previously unknown mammalian molecule can reprogram the mitochondrial energy supply route to become independent of oxygen reducing toxic byproduct levels. This project will explore how this alternative energy pathway changes with age and whether activating it can restore mitochondrial health in older mice. By tracing metabolic changes in reprogrammed mitochondria, the goal is to find out if this “low-damage” energy mode can slow or even reverse some of the effects of aging. This could lead to new ways to support healthy aging at the cellular level.

Zoonotic transmission of avian Influenza A virus (IAV) to humans poses a pandemic threat. Recent transmission of avian IAV to dairy cattle, and to dairy farm employees emphasizes the importance of identifying molecular mechanisms that regulate zoonotic events. It is thought that the IAV envelope glycoprotein, hemagglutinin (HA), must adapt its receptor specificity to bind α2,6-linked SA that predominates the human upper airway to initiate infection. However, recognition of α2,6-linked SA by HA is insufficient for avian H5N1 IAVs to enter human cells, indicating that other adaptations are necessary for zoonotic transmission to occur. Although evidence suggests that the pH and temperature sensitivity of HA are important factors that govern host tropism of IAV, a molecular mechanism that explains the temperature and pH dependence is missing. To define the pH and temperature dependence of HAs pre- to post-fusion conformational change, we first focused on visualizing conformational dynamics of HA with single-molecule FRET (smFRET). Preliminary data reveal that under neutral pH and room temperature conditions, the head domains of A/Vietnam/1194/2004 (H5N1) (VN04) HA, HA1, undergo a breathing motion where the heads are either caged, or uncaged. At pH8.0 HA spends more time in the fully caged conformation and less time in the uncaged conformation. Decreasing the pH to 6.5 shifts the equilibrium to where HA spends more time in the caged conformation and 80% of the time in the uncaged conformation. These data allow us to establish a conformational phenotype for HA where can determine the pH and temperature dependence of a given conformational phenotype. Thus, the central hypotheses of this proposal are that (1) the regulation of the pre- to post-fusion conformational change of avian HA is differentially regulated by pH and temperature compared to human adapted HA and (2) the membrane fusion phenotypes of HA are different. Experiments performed in Aim 1 will characterize the pH and temperature dependence of HAs conformational phenotype by monitoring conformational dynamics of HA at pH 8.0, pH 6.5, and pH 5.5 as well as at room temperature, 32°C and 37°C. I will implement the smFRET for three HA serotypes: A/Vietnam/1194/2004 (H5N1) (VN04), A/California/07/2009 (H1N1) (CA09) and A/Hong Kong/1/1968 (H3N2) (HK68). Furthermore, mutations that alter pH and temperature stability will be characterized to evaluate a molecular mechanism that can explain the differences in the conformational phenotype between the different HA serotypes. Aim 2 will characterize the pH and temperature dependence of HA-mediated membrane fusion by monitoring the extent and rates of fusion of HA pseudo-typed virus with the three previously mentioned HA serotypes. Additionally, the same pH and temperature stability mutations will be used to assess their impact on membrane fusion. Collectively, these data will reveal a mechanism that explains the zoonotic transmission potential of IAV and help improve genetic surveillance efforts.

In the context of human immunodeficiency virus (HIV), both CD4+ T cells and macrophages contribute to the viral reservoir within people living with HIV on combination antiretroviral therapy. Natural killer (NK) cells are the major cytolytic cells of the innate immune system, and their failure to effectively eliminate infected cells allows propagation and persistence of infection. In in vitro models of infection, HIV-infected macrophages are more resistant to NK cell-mediated killing than their CD4+ T cell counterparts, implicating macrophage-specific mechanisms of resistance. However, these mechanisms have yet to be determined. The overall objective of this proposal is to define macrophage-specific mechanisms that facilitate increased resistance to NK cellmediated killing. The central hypothesis is that HIV-infected macrophages resist NK cell-mediated killing by reducing immediate NK cell lytic function, and antagonizing death receptor signaling. To address this hypothesis, the following aims will be pursued: Specific Aim #1 will characterize release of HIV-infected macrophage lysosomal granules towards NK cells. Published work shows that melanoma cells being targeted by CD8+ cytolytic T lymphocytes release their lysosomes at the immunological synapse to degrade perforin, protecting them from elimination. To measure lysosome release, the investigators used CD107a, which lines the membrane of lysosomes and lytic granules and is surface exposed following degranulation. My preliminary data shows that HIV-infected macrophages increase surface CD107a expression upon co-culture with autologous NK cells. Therefore, I will investigate whether this mechanism is also being used by HIV-infected macrophages to neutralize NK cell degranulation. Specific Aim #2 will define mechanisms of HIV-infected macrophage resistance to NK cell FasL-mediated killing. Preliminary data shows that HIV-infected macrophages, but not CD4+ T cells, are not susceptible to apoptosis induced by incubation with recombinant FasL, despite both cells expressing the Fas receptor. I will investigate whether this resistance is due to increased anti-apoptotic activity of the protein cFLIP, which regulates caspase-8 activity. To complement these in vitro experiments, I will also analyze published single-cell RNA-sequencing data sets to determine tissue resident macrophage expression of cFLIP and other anti-apoptotic proteins. Results from these studies will elucidate how HIV-infected macrophages escape NK cell-mediated killing and will ultimately inform clinicals strategies utilizing NK cells to control pathogenesis. The work outlined above will be conducted at the University of Massachusetts Chan Medical School, within the Immunology and Microbiology Ph.D. program. The training plan, which will help me achieve my goal of becoming an independent investigator, includes coursework on basic/advanced principles of immunology and ethics of research. Finally, I will attend national/international conferences where I will be able to receive feedback from external scientists on my research and engage with others performing cutting edge research.

Despite progress in pharmacological advances, the rate of obesity incidence rises every year with an increased risk of developing insulin resistance, cardiovascular disease, and other cardiovascular risk factors including type 2 diabetes (T2D). Current treatments are not curative and typically require compliance with life-long, daily treatments. Thus, there is a critical need for novel therapeutic advancements to combat obesity and its comorbidities. We plan to generate metabolically active, thermogenic adipocytes from human white adipose tissue (WAT) to advance a cell therapy strategy for alleviating insulin resistance and cardiovascular risk in T2D. Using a CRISPR-based system to target a thermogenic suppressor gene, Nrip1/RIP140, we were able to induce "browning" in mouse and human white adipocytes with high efficiency. The browning of WAT is favorable as the brown-like human adipocytes express a brown fat-specific marker, uncoupling protein 1 (UCP1), and other beneficial secreted factors that can improve metabolism in obese mice. Although our published method is effective in vivo, we only manage to achieve ~10% of the brown fat UCP1 expression, implying that there is room for more browning to generate a more potent thermogenic fat. PPAR and cAMP signaling are key in the activation of brown fat. Thus, our goal is to generate fully brown adipocytes from human white adipocytes by combining Nrip1 disruption with PPAR and cAMP activation. We predict that this combination will result in maximally induced brown human adipocytes that can improve systemic metabolism in our mouse model. The long-term goal in our lab is to genetically modify human adipocytes ex vivo to enhance therapeutic activity and implant the metabolically active and thermogenic adipocytes into obese patients.

Neurodegenerative diseases (NDDs) are devastating conditions that rob individuals of their cognitive function, mobility, and ability to function in the world. Ultimately, many of these diseases are fatal. Today, a combined 6.5 million Americans suffer from NDDs, encompassing Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). However, by 2030, 1 in 5 Americans will be over the age of 65, and because NDDs strike primarily in mid- to late-life, the incidence is expected to soar as our population ages. These circumstances highlight the increasing urgency for the development of effective treatments and cures for NDDs, which are currently lacking. While NDDs differ in their inciting mechanisms, research has now clearly demonstrated the presence of shared features of downstream pathophysiology, notably, the role of a dysregulated neuroinflammatory system. Recent studies in humans and animal models have uncovered a population of microglia (Disease-associated microglia, DAMs), that are defined by a distinct transcriptional signature, and are conserved across several different NDDs. Intriguingly, the DAM signature includes upregulation of a number of different members of the MS4A gene family, for which polymorphisms have been linked to AD by numerous genome-wide association studies (GWAS). The upregulation of AD-associated MS4A genes in DAMs begs the questions of whether MS4A genes might play a common role in NDDs, which share a DAM signature, and furthermore, whether MS4A genes impact the functional properties of microglia in the context of NDDs. Excitingly, our lab has found that across three animal NDD models (5XFAD, MAPT, SOD1G93A), mice deficient for either of two individual Ms4a family members exhibit improved disease phenotypes, extension of lifespan, and amelioration of histopathological disease hallmarks. Thus, this proposal will test the hypothesis that multiple MS4As act in concert to drive pathology in a mouse model of ALS and regulate microglial transcriptional as well as functional responses to the NDD milieu. To test this hypothesis, aim 1 will investigate the impact of simultaneous deletion of the entire MS4A gene family on ALS. To this end, we have generated a novel mouse genetic reagent in which the entire MS4A gene cluster is deleted. These mice will be crossed to the SOD1G93A ALS mouse model and pathological features of ALS, including motor defects, lifespan, microgliosis, neuronal loss, and synapse elimination will be assessed. Aim 2 will examine the impact of MS4A deficiency on the transcriptional and functional properties of spinal cord microglia isolated from end-stage SOD1G93A mice. Specifically, I will utilize single-cell RNA sequencing (scRNA-seq) in tandem with spatial transcriptomics (MERFISH) to evaluate the impact of MS4A deletion on the DAM population. In parallel, I will examine how MS4A deficiency in vivo affects the key microglial function of phagocytosis. Together, these aims will provide fundamental new insight into the role of MS4As in ALS and contribute to the development of therapeutic approaches targeting MS4A receptors.

The sliding clamp (PCNA) is an interaction hub for over one hundred protein partners during DNA replication, DNA repair, and DNA recombination, among other tasks. PCNA is a planar ring that slides along DNA and serves as a scaffold for enzymes that act on DNA. PCNA is loaded onto DNA by the "clamp loader" RFC protein complex. Despite the fact that clamp loading is essential to all life, we still do not fully understand its core molecular mechanisms. I use structural biology, biochemical and computational characterization to understand how RFC regulates its clamp loading process.

During obesity, white adipose tissue (WAT) expands to store excess calories from the diet. WAT expands either by increasing the size of preexisting adipocytes (hypertrophy) or by increasing the number of adipocytes through the differentiation (hyperplasia). Hypertrophic growth has been associated with hypoxia (low oxygen (O2)) in WAT due to ineffective vascularization during its expansion. Hypoxia in WAT has been linked to insulin resistance, ectopic lipid deposition, and mitochondrial dysfunction, although the mechanisms connecting hypoxia to these effects are not well understood. A major function of O2 is that it serves as the terminal electron acceptor (TEA) in the electron transport chain (ETC), which sustains mitochondrial functions including de novo pyrimidine synthesis, reactive oxygen species production, and ATP generation. However, it is unknown how obesity-induced hypoxia impacts the ETC, and if these changes mechanistically explain adipocyte dysfunction upon obesity. In preliminary work, we discovered rhodoquinone (RQ), a novel mammalian metabolite that functions as an electron carrier in the ETC. The RQ-directed ETC circuit employs fumarate, instead of O2, as the TEA, enabling the RQ circuit to support certain mitochondrial functions in hypoxia. Through lipidomic analysis of tissues from two distinct obese mouse models, we found that RQ levels profoundly and specifically rise in the WAT of obese mice. These data inspired the hypothesis that obese adipose tissue reprogram their ETC to the RQ/fumarate circuit to support mitochondrial functions in WAT during hypertrophic/hypoxic expansion. To address this hypothesis, Aim 1 will leverage primary human adipocytes to explore how the RQdirected ETC circuit impacts differentiation and lipid droplet formation. This will be achieved using stable isotope tracing to measure lipogenesis and western blotting to monitor signaling cascades associated with lipid droplet formation and turnover. In Aim 2 we will test which ETC circuit (UQ/O2 or RQ/fumarate) is preferentially used in the WAT of lean versus obese mice. To this end, we will perform stable isotope tracing assays and respirometry experiments that distinguish these two ETC pathways in vivo. Moreover, this aim will test the therapeutic potential of reprogramming the ETC to the RQ/fumarate circuit during diet-induced obesity using small molecule analogs of RQ. We will determine the impact of RQ on insulin sensitivity, lipid storage, and metabolic parameters via metabolic cages in lean and obese conditions to reveal if RQ can mitigate obesity-induced metabolic dysfunction. Taken together, this work will explore the role of a novel mammalian metabolite in adipocytes during differentiation and upon obesity induction. Beyond defining the fundamental metabolic changes induced by the RQ circuit in differentiating adipocytes, the proposed research is translational, as it will investigate, for the first time, the therapeutic potential of reprogramming the ETC in diet-induced obesity.

Opioid addiction is a major public health crisis, with many individuals experiencing both dependence and sleep disturbances. These disturbances, such as poor sleep quality and disrupted sleep rhythms, make recovery more difficult by increasing cravings and the risk of relapse. Our study examines how opioid addiction affects molecular rhythms in the human brain. In the first part of our research, we will study post-mortem brain tissue from individuals with opioid use disorder. We will use advanced techniques to analyze how molecular rhythms differ across various types of brain cells, focusing specifically on the striatum, a key region involved in reward and motivation. By comparing individuals with and without opioid use disorder, we aim to identify cell-type-specific changes in the brain associated with addiction. In the second part of the study, we will use a preclinical mouse model to observe how disruptions in molecular rhythms in the brain can influence addiction-like behaviors and sleep patterns. We will monitor sleep using specialized brain recordings called EEG and EMG (electroencephalography and electromyography) and measure the animals’ motivation to seek opioids. Our goal is to better understand the link between disrupted brain rhythms, opioid addiction, and sleep disturbances. This research may help identify new treatment strategies that improve recovery and reduce relapse by targeting sleep and circadian rhythms.

Familial dilated cardiomyopathy (DCM) is a heritable disorder characterized by progressive enlargement of the heart's ventricles and impaired contraction, often leading to early-onset heart failure. A significant subset of inherited DCM cases is attributed to mutations in an 18-bp segment of the RNA binding motif protein 20 (RBM20) gene, which causes aberrant splicing of critical cardiac genes. While current treatments offer symptomatic relief, there is an unmet need for therapies that correct the underlying genetic cause. This project seeks to develop a universal CRISPR gene editing strategy to replace the entire 18-bp RBM20 pathogenic cluster with a synonymous DNA sequence. The approach utilizes prime editing (PE), focusing on the optimization of the PE3b system, which has been identified as a promising strategy for achieving high precision and low indel rates. This optimization is being conducted via a high-throughput, self-targeting lentiviral screen to identify optimal guide RNA configurations. The optimized designs identified through this screen will then be validated in isogenic induced pluripotent stem cell (iPSC) lines carrying pathogenic RBM20 variants and differentiated cardiomyocytes (CMs) to assess restoration of normal cellular phenotype. This work will inform the development of an efficient, safe PE platform to treat genetically diverse cases of RBM20-DCM.

The germline contains the genetic information that will be passed to future generations. Therefore, maintaining the germline genome is essential for fertility and species survival. One mechanism of germline genome maintenance is that of the PIWI/piRNA pathway, in which small RNAs known as piRNAs interact with a PIWI Argonaute protein to form what is known as a piRNA-Induced Silencing Complex (piRISC). Through its endonuclease activity, piRISC silences repetitive elements (i.e., transposons) to protect the genome for future generations and regulates gene expression to ensure proper germ cell development and function. Loss of PIWI function leads to infertility in at least one sex in many animals, including human males. Recent work has revealed that the small zinc-finger protein, gametocyte-specific factor 1 (GTSF1), accelerates piRISC target cleavage. Loss of GTSF1 function in mice and human males leads to infertility. Preliminary kinetic evidence suggests that GTSF1 is not required for target binding or target release. However, the piRISC catalytic states associated with GTSF1 binding have not been explored. Seven GTSF1 residues have been identified as key for target cleavage, but most of these amino acids are not conserved in the other mouse GTSF paralogs, GTSF1L and GTSF2, even though they also accelerate piRISC target cleavage. This proposal seeks to test the hypothesis that mammalian GTSF proteins stabilize a catalytically active state of piRISC via key contacts with both the piRNA-target RNA duplex and PIWI protein. Aim 1 will use single-molecule FRET to probe piRISC conformational changes in the absence and presence of GTSF proteins to determine which, if any, catalytic state is stabilized in the presence of GTSF. Aim 2 will employ a high-throughput screening method to identify all amino acid positions across GTSF paralogs which are required to interact with piRISC. This study will provide insights into how GTSF1 accelerates piRISC target cleavage and determine which GTSF residues are key for its function, providing insight into why some human GTSF1 mutations lead to infertility. The proposed research will provide training in microscopy, in vitro biochemistry, and bioinformatics to prepare the fellow for a postdoc studying epigenetic inheritance and a future career as an independent investigator.

Immunotherapies such as PD-1 and CTLA-4 inhibitors have transformed cancer treatment, yet many patients remain unresponsive, underscoring the need for new ways to engage the immune system. This project investigates NLRP10, a highly expressed but poorly characterized inflammasome sensor in skin cells. Our studies show that a fungal metabolite induces mitochondrial stress sensed by NLRP10, triggering IL-1 cytokine release, cell death via pyroptosis, and immune cell recruitment and anti-tumor activity in melanoma models. We propose that NLRP10 functions as a mitochondrial damage sensor linking epithelial stress responses to tumor immunity. This research will define how NLRP10 detects mitochondrial danger signals and regulates inflammation and tumor control, revealing a previously unrecognized immune pathway at the skin–tumor interface. Ultimately, uncovering the biology of NLRP10 will expand our understanding of how innate immunity shapes skin cancer outcomes and may open new avenues for developing therapies that reprogram the tumor microenvironment to enhance anti-cancer immunity.

Synthetic messenger RNAs (mRNAs) represent a new class of biopharmaceuticals with broad clinical utility for a range of diseases. The incorporation of chemically modified uridine nucleosides, pseudouridine (Ψ) and N1-methylpseudouridine (m1Ψ), significantly reduces synthetic mRNA immunogenicity. Linear nucleoside-modified mRNAs are short-lived because they are susceptible to cellular exonucleases, hindering their broad clinical utility for a range of diseases. Synthetic circular mRNAs (circRNAs) evade cellular exonucleases, resulting in a longer half-life, but efficient circularization methods are incompatible with chemical modifications. The most efficient method of RNA circularization utilizes self-splicing group I introns. Proper folding—and thus activation—of the typical group I intron is disrupted by Ψ-modified nucleotides. A survey of self-splicing introns, however, identified a compact group I intron from the cyanobacterium Azoarcus that effectively circularizes short (~150 nt) Ψ-modified RNA. The Azoarcus intron can circularize long (~2000 nt) unmodified mRNA but not long Ψ-modified RNAs. This proposal seeks to test the hypothesis that Ψ and m1Ψ prevent circularization by disrupting tertiary interactions required for rapid and efficient intron splicing and to develop efficient circularization techniques compatible with Ψ and m1Ψ for safe and stable RNA therapeutics. Aim 1 will determine how uridine modifications affect the structure of Azoarcus group I intron. High throughput structural probing will be used to study how uridine modifications stabilize inactive conformations of the Azoarcus group I intron. Aim 2 will employ in vitro evolution to identify Azoarcus group I intron variants optimized to circularize Ψ and m1Ψ-modified RNA. The Ψ- and m1Ψ-modified circRNA will be tested in immune cells for their ability to induce an immune response. This study will provide structural insights into how nucleoside modifications change RNA structure and function and develop a straightforward methodology to prepare nucleoside-modified circular mRNAs, expanding the potential uses of mRNA therapeutics beyond vaccines. In addition, the proposed research will provide training in high-throughput sequencing, in vitro biochemistry, cellular RNA sensing, nucleic acid chemistry, and structural biology to prepare the fellow for a career as an independent investigator developing next-generation mRNA therapeutics.

While there are many FDA-approved therapies to treat relapsing-remitting multiple Sclerosis (MS), there are far less options for treating neurodegeneration in progressive disease. Intriguingly, similar to other neurodegenerative diseases (e.g. Alzheimer’s disease and frontotemporal dementia), a hallmark feature of progressive disease in MS is the loss of synapses and gray matter atrophy. Our lab recently discovered a striking loss of synapses in the visual thalamus of MS patient tissue and MS-relevant mouse and marmoset models concomitant with visual impairment. This was particularly intriguing since prolonged visual impairment is historically attributed to demyelination of the optic nerve and is a frequent occurrence in MS patients. As complement proteins were previously shown to mediate synapse elimination by phagocytic microglia in neurodegenerative disease and genetic variants in complement proteins have recently been correlated with visual impairment in MS patients, Dr. Schafer’s lab has been exploring this pathway in synapse loss in the visual thalamus in MS. First, Dr. Schafer’s lab showed that complement proteins C1q and C3 were both increased in a mouse and non-human primate model of MS (experimental autoimmune encephalomyelitis, EAE). However, unlike in development, C1q did not localize to synapses in this context. Instead, C3 was highly synaptic in EAE to induce microglia-mediated phagocytosis and elimination of synaptic material. In contrast to C3 at synapses, Dr. Reich and Dr. Schafer identified that C1q was particularly high in microglia surrounding chronic active MS lesions and loss of C1q in microglia in the mouse EAE model attenuated the inflammatory response of microglia. Still, it is unclear how C1q is modulating inflammation, and whether C1q is working upstream of C3 to regulate synapse loss or if synapse loss is occurring through the alternative pathway, independent of C1q. Also, there are many other molecules that regulate complement proteins and it is unclear how many of these complement-related proteins contribute to MS-related disease. Therefore, the overall goal of this proposal is to gain a more comprehensive understanding of how complement proteins are regulated in demyelinating disease.

Mycobacterium tuberculosis (Mtb) poses a paradox: despite its seemingly stable genome, it is highly adaptable. Historically, Mtb was viewed as genetically stable, lacking horizontal gene transfer (HGT) and accumulating single-nucleotide variants (SNVs) at a slow rate (~1x10^-7 SNV/site/year). Yet, it adapts to diverse environments, evades immune responses, and withstands antibiotics. The genetic basis for this adaptability remained unclear until recent studies highlighted transient phase variation as a crucial factor. Our previous work identified frequent genetic variation in simple sequence repeats (SSRs) within the Mtb genome (glpK), which is linked to drug resistance and reduced drug efficacy. In addition to this, a phylogenetic analysis of over 31,000 clinical isolates identified 121 SSR sites, including glpK, with a high INDEL rate likely driven by positive selection, with 44 SSRs showing more variation than expected under neutral evolution. In this grant proposal, we plan to leverage a recently generated library of strains representing each of these clinically prevalent mutations to quantify the effect of each on the bacterium’s sensitivity to antibiotics. Understanding these mechanisms comprehensively could reveal new therapeutic strategies targeting antibiotic-resistant subpopulations, potentially improving treatment success and reducing therapy duration.

Vitiligo is characterized by loss of epidermal melanocytes and an interface dermatitis with IFN-γ–driven T cell infiltration. Although melanocyte antigens are well characterized in melanoma, the antigens that drive autoimmunity in vitiligo remain unclear, in part because melanocytes are depleted in lesional skin. I hypothesize that inflammatory and injury-induced stress remodel the repertoire of peptides presented by MHC class I on melanocytes, generating neoepitopes that prime autoreactive T cells. To test this hypothesis, I will (1) map melanocyte and immune-cell states in patient-derived samples and in a vitiligo mouse model using single-cell RNA-seq and multiplex imaging; (2) define the melanocyte MHC class I peptidome by LC–MS/MS at baseline and after IFN-γ stimulation; (3) identify expanded and public TCR clonotypes and pair TCRs with cognate peptides using reporter assays; and (4) evaluate the pathogenicity of peptide-specific T cells in vivo. These studies will identify melanocyte-derived peptides that initiate disease, delineate how inflammation reshapes antigen presentation, and nominate precise therapeutic targets for intervention in vitiligo.

Due to unpublished data, a summary is not currently available.

Treating PTSD in Primary Care: Findings from a New Pragmatic Trial

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive form of leukemia that primarily affects children. While many pediatric patients reach sustained remission, about 20% relapse. Relapse is thought to be due to a rare, chemotherapy-resistant subpopulation of cells, termed leukemia initiating cells (L-ICs), that enter quiescence and survive chemotherapy, after which they can exit quiescence, proliferate and re-establish disease. As such, effectively targeting L-ICs represents a potential therapeutic approach to prevent T-ALL relapse. Our preliminary data suggest that BTG2, an activator of mRNA deadenylation, plays a critical role in maintaining L-IC quiescence by destabilizing Myc and potentially other cell cycle-related mRNAs. Interestingly, BTG2 is downregulated in relapsed T-ALL patients, leading us to hypothesize that the resulting upregulation of key BTG2 target mRNAs could promote L-IC activity and thus represent potential therapeutic targets. In this project, I will comprehensively identify BTG2 target mRNAs in human T-ALL cell lines using RNA-seq and poly-A tail length sequencing (PAL-seq) methodologies, and validate candidates for their ability to promote L-IC activity. Future experiments will test whether knocking down BTG2 target mRNAs improves survival in T-ALL xenografted mice. The insight gained by these studies is likely to have significant clinical relevance for high-risk T-ALL patients that currently have few targeted treatment options.

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The overall goal of this proposal is to gain a new understanding of the factors that contribute to chemoresistance in BRCA1 and BRCA2 (BRCA) mutant hereditary breast and ovarian cancers (HBOC). Currently clinical strategies rely on chemotherapies and poly (ADP-ribose) polymerase inhibitors to control malignant disease. Unfortunately, tumor chemoresistance frequently occurs which necessitates studies that uncover the critical factors leading to chemoresistance. We have recently discovered chemoresistance is linked the single-stranded (ss)DNA gap suppression in multiple models of HBOCs and patient tumors. Our work has generated a paradigm shift that ssDNA predicts sensitivity whereas gap suppression predicts resistance. To expand upon our model that ssDNA gaps are the sensitizing lesions in BRCA cancers, I propose two aims. In Aim 1, I will determine if an axis of chemoresistance in BRCA1 deficient cancers, linked to restored homologous recombination, is instead mediated by gap suppression. In Aim 2, I will determine if gap suppression in a chemoresistant BRCA2 tumor model is linked to the activation of translesion synthesis and how translesion synthesis can be overcome to resensitize these cancers. Together, these aims increase our knowledge of the basic factors that lead to chemoresistance in the clinic and will provide new insights into the vulnerabilities unique to BRCA deficient cancers. Moreover, by identifying unique factors contributing to chemoresistance, we will develop an understanding for potential druggable targets and biomarkers for future personalized chemotherapy. Existing chemotherapies are constrained by their side-effect profiles, often taxing patients' tolerance and potentially inducing secondary malignancies. Generating a new understanding of the factors contributing to chemoresistance is pertinent to improving patient outcomes.

The goal of this project is to determine the mechanisms by which interferon gamma (IFNg) signaling promotes tumor growth and immune suppression to drive neuroendocrine prostate cancer (NEPC) progression and resistance to immune checkpoint blockade (ICB) therapies. Following hormone therapy failure, some patients develop an aggressive subtype of prostate cancer known as NEPC that is lacking in effective treatment options. Though most prostate cancers are defined by a “cold” tumor microenvironment (TME) lacking T cells that mediate anti-tumor immunity and are necessary for immunotherapy responses, it was recently shown that a subset of NEPC patient tumors are “inflamed” with T cells and have heightened expression of interferon gamma (IFNg) signatures. As IFNg is associated with activation of adaptive immunity and better ICB outcomes, this suggests that NEPC patients may potentially benefit from immunotherapy. To determine the impact of IFNg on tumor- immune interactions in situ, I developed a novel mouse model of NEPC through in vivo electroporation of CRISPR constructs targeting three tumor suppressor genes, Pten, p53, and Rb1 (PtPRb), commonly disrupted in NEPC patients. Despite PtPRb NEPC tumors recapitulating the inflamed TME of human NEPC with enhanced IFNg signaling and a significant influx of CD8+ T cells, paradoxically, mice failed to respond and even had worse survival following anti-PD-1 ICB. Inhibiting Nuclear Factor kappa B (NFkB) signaling downstream of IFNg in NEPC cell lines in vitro or blocking the IFNg receptor (IFNGR1) in NEPC tumors in vivo not only inhibited tumor growth and prolonged survival, but also reduced the numbers of macrophages that highly infiltrate NEPC tumors and can suppress T cell and immunotherapy responses. Based on these preliminary results, our central hypothesis is that IFNg signaling contributes directly to tumor growth and macrophage dysfunction, and that targeting it will activate immunotherapy responses in NEPC. In Aim 1, we will test whether IFNg signaling directly contributes to NEPC viability and growth signaling. Genetic and pharmacological approaches will be used inhibit different upstream and downstream IFNg signaling regulators in murine NEPC tumor cells and human NEPC organoids to investigate their role in driving growth factor signaling and growth phenotypes in vitro and in vivo. In Aim 2, we will test whether IFNg drives macrophage-mediated immune suppression and immunotherapy resistance. The impact of IFNGR1 KO on macrophage polarization, phenotypes, and T cell interactions will be assessed in vitro by tumor-immune co-culture assays and in vivo in murine NEPC tumor models by multiplexed error-robust fluorescence in situ hybridization (MERFISH) spatial transcriptomics. Finally, we will evaluate the effects of macrophage or IFNGR1 blockade on tumor and immune responses and anti-PD-1 ICB outcomes in our preclinical NEPC animal models. Ultimately, this work will not only unveil new tumor intrinsic and extrinsic mechanisms by which IFNg signaling drives NEPC progression, but also advance novel strategies targeting IFNg regulators to enhance immunotherapy outcomes in this aggressive disease.

TinyMCE updated how iframes are created within the WYSIWYG editor when embedding forms or videos. This is to follow security best practices. This video provides instructions on a workaround, until this is fixed within the WYSIWYG editor, using an HTML block that can be dropped into the WYSIWYG in place of the iframe.

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Dominic has been in and out of hospitals his entire life. His artwork focuses on personal interactions with the healthcare system and his experiences dealing with chronic illness.

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Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer, with a mere 13% average 5-year survival rate. Conventional chemotherapy and immunotherapy regimens have limited effectiveness, and surgical resection of the tumor is not viable for the majority of PDAC patients diagnosed with advanced metastatic disease. Our previous research has shown therapeutic induction of cellular senescence with RAS pathway targeting therapies can induce cytokine and chemokine production through the senescence-associated secretory phenotype (SASP) that can effectively activate anti-tumor T cell immunity and responses to anti-PD-1 immune checkpoint blockade. To build on these findings and overcome limitations associated with senescence-inducing therapy toxicity, here we leveraged mRNA technology to deliver specific SASP cytokines and chemokines we have found to stimulate immune responses into the suppressive PDAC TME as an immune oncology platform. We created an in vitro transcription pipeline for mRNA production and have successfully demonstrated delivery of multiple mRNAs simultaneously into the TME of transplanted and autochthonous PDAC mouse models, stimulating the local production of cytokines normally absent in PDAC. We further characterized a novel combination of five cytokines and chemokines that can effectively recruit and activate both innate and adaptive immune responses against PDAC. Considering the recent success of off-the-shelf neoantigen mRNA vaccines in early human PDAC patient trials, we have now developed mRNAs that encode PDAC-specific antigens. By integrating our cytokine mRNA platform with antigen mRNAs, we observe a significant increase in intratumoral antigen-presenting dendritic cell populations, leading to substantially enhanced T-cell-mediated anti-tumor immune response. Long-term studies in autochthonous PDAC mouse models demonstrate that combining cytokine and antigen mRNAs can completely eradicate tumors in select cases, resulting in significantly extended survival. Overall, this study not only unveils pivotal insights into the cytokines absent in PDAC that are crucial for promoting anti-tumor immunity but also pioneers an innovative immunotherapy approach.

UMass Chan Biochemistry and Molecular Biotechnology (BMB) Department quarterly newsletter for March 2025. The newsletter includes a list of new hires, upcoming events and seminars, information about this month's Anti-Racism Reading Club, department news, a link to the feature of the month, recent blog posts, a list of recent publications, wellness tips, and departmental job openings.

Meet UMass Chan BMB Administrator III, Dr. Suresh Kannan!

Understanding how to fix the accessibility issues in the CMS that are noted in Siteimprove.

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Massachusetts is considering legislation called Primary Care for You (PC4YOU) that could have a national impact as the country deals with the challenges of access to primary care.

UMass Chan Biochemistry and Molecular Biotechnology (BMB) Department newsletter for December, 2024.

Meet UMass Chan BMB postdoc, Janneke Icso from the Kelch Lab!

Marlina Duncan, EdD, vice chancellor for diversity and inclusion, reminds the UMass Chan community that our diversity is central to our mission.

Transforming Chronic Pain Care: Insights from Dr. Sarah Pearson

Human T-cell leukemia virus type-1 (HTLV-1) is an oncogenic human retrovirus affecting over 20 million people worldwide. HTLV-1 infection can cause adult T-cell lymphoma (ATL) and other serious inflammatory diseases. Estimates report that 5-10% of HTLV-1 infected patients will develop a serious condition such as ATL, which has poor 4-year survival and high relapse rates. HTLV-1 has persistent infection rates across the globe and reaches up to 45% prevalence in certain communities. Despite this impact on human health, there are no direct-acting antivirals (DAAs) or vaccines against HTLV-1. HIV-1 and HTLV-1 are from the same viral family and encode for a homodimeric aspartyl protease crucial for cleavage of functional proteins from viral polyproteins. The activity of HIV-1 and HTLV-1 protease is essential to their viral life cycles. The Schiffer laboratory has extensive experience with viral protease crystallography and inhibition, especially with viral proteases for HIV-1, HCV NS3/4A, and SARS-CoV-2 main protease. This expertise uniquely positions me to design, synthesize, and characterize potent, resistance-thwarting protease inhibitors against HTLV-1 protease. Resistance-preventing DAA design is essential because of the selective pressure applied during DAA treatment. An ideal and proven strategy for developing a highly potent and resistance-preventing viral protease inhibitor is to target the active site through rational design using the substrate envelope. The substrate envelope for HTLV-1 protease has not been characterized and we lack a detailed understanding of the protease substrate specificity. I hypothesize that by translating strategies from our design of HIV-1 protease inhibitors, namely characterizing HTLV-1 protease’s substrate specificity, I can design potent and resistance-preventing DAAs for HTLV-1 protease. Aim 1: Characterize the structural basis for HTLV-1 protease substrate specificity. HTLV-1 protease cleaves six substrates by recognizing cleavage sites between individual proteins of the viral polyprotein. I will investigate the molecular basis of this recognition underlying protease specificity by determining cocrystal structures of the protease with bound substrates. The conserved volume inhabited by the substrates will define the substrate envelope and inform inhibitor design for HTLV-1 protease. Aim 2: Rationally design, synthesize, and characterize inhibitors of HTLV-1 protease to optimize potency. HIV-1 and HTLV-1 proteases share an active site amino acid sequence identity of 45% and high structural similarity. Therefore, I will begin inhibitor design by testing a selection of our in-house HIV-1 protease inhibitors, which have already shown low (1 µM) to moderate (30 nM) potency against HTLV-1 protease. I will combine experimental inhibition assays with cocrystal structure analysis to identify lead compounds for inhibitor design. I will leverage substrate specificity of the protease by moving inhibitor design towards compounds that mimic the shape of substrates, leveraging the substrate envelope (Aim 1), and the interactions between protease and substrate. I aim to produce novel, highly potent (sub-nM) inhibitors that will be promising DAAs for further investigation against HTLV-1.

Huntington’s Disease – a devastating neurodegenerative condition – is caused by a defect in the Huntingtin gene, resulting in the production of alternative forms of Huntingtin mRNA and protein. This proposal will use small RNA drugs to reduce alternative forms of Huntingtin in mouse models of Huntington’s disease and determine the effect on disease features and outcomes. Findings from these studies will provide insight into the mechanisms underlying Huntington’s Disease to inform the development of future therapeutics.

Mitochondria are essential for cell health and survival. Understanding the quality control machinery that mitochondria employ to maintain a healthy network is critical for health and disease. Our lab recently showed the role that lipid transfer protein Vps13D plays a critical role in mitochondrial clearance by autophagy (mitophagy) in the Drosophila developing midgut. Vps13D has been implicated in human movement disorders, highlighting the importance of understanding how it controls this process. Importantly, we do not know what proteins Vps13D may be interacting with at the mitochondrial surface to facilitate mitophagy. I performed an RNAi screen against mitochondrial genes that were shown to physically interact with Vps13D in human cells. I discovered that Mtch, the fly homolog of MTCH2, phenocopies both mitochondrial and autophagic defects that Vps13D mutants display, including failure to clear mitochondria, autophagic cargoes like p62, and the autophagy protein Atg8a. I generated a null mutant for Mtch, which displays phenotypes similar to what is observed by Mtch knockdown with RNAi and Vps13D mutants. Importantly, Mtch mutant cells exhibit a robust decrease in Vps13D protein puncta. I plan to use this Mtch mutant to: (1) characterize the function of Mtch in mitophagy, (2) determine the relationship between Mtch and Vps13D in mitophagy, and (3) investigate the relationship between Mtch and known regulators of autophagy and mitophagy. These studies will advance the field by creating a better understanding of mitophagy, and will also provide a novel genetic pathway to study that could lead to targeted therapies to correct mitochondrial disorders.

RNAi-based drugs are emerging as a new class of therapeutic modalities that are transforming pharmaceutical development. The National Institute of Arthritis and Musculoskeletal and Skin Diseases has granted a K99/R00 Pathway to Independence Award to Dr. Qi Tang to support his career transition to an independent principal investigator position at a U.S. academic institution and to fund his research on developing a programmable siRNA-based therapeutic platform for gene silencing in the skin. Dr. Tang will receive integrated scientific and career training during his K99 phase at UMass Chan, and in R00 phase, he will work to establish his independent laboratory with a focus on designing and expanding the utility of siRNA therapeutics for treating inflammatory skin diseases that currently lack sufficient treatments or are undruggable by conventional modalities.

Down syndrome (DS) is caused by trisomy for human chromosome 21 and affects more than five million individuals worldwide. Autism spectrum disorder (ASD) is a common co-occurring condition in persons with DS. Because individuals with DS-ASD often present with deleterious behaviours, such as self-injurious behaviour, aggression, sleep disturbances, and feeding difficulties, identifying effective treatments for the behavioural sequelae of DS-ASD has the potential to improve quality of life for individuals with DS and their caregivers. However, recent research has focused on diagnosing DS-ASD and describing its behavioural profile. The underlying molecular mechanisms that contribute to DS-ASD risk remain unexplored. Other DS-associated phenotypes likely result from dysregulation of the Sonic hedgehog (Shh) signalling pathway, which is a critical developmental pathway. Because Shh signalling is required for the differentiation of serotonergic neurons and because the serotonergic system is implicated in the pathogenesis of ASD, we hypothesized that disruption of Shh could result in behavioural phenotypes relevant to ASD. To address this hypothesis, we will perturb Shh signalling in developing zebrafish and assess serotonergic neuron morphology, overall brain structure, brain activity, and behaviour. How trisomy 21 contributes to misregulation of Shh also merits further study. Based on a previous screen of chromosome 21 genes, we selected HMGN1 as a likely regulator of Shh. We will overexpress HMGN1 and explore its effects on Shh signalling, serotonergic neurons, behaviour, gene expression, and epigenetic modifications. Successful completion of this project will lay the foundation for drug screens relevant to DS-ASD and cognition in larval zebrafish models.

Negative affect and stress experienced during alcohol abstinence can be a major factor contributing to relapse in alcohol use disorder, yet underlying neurobiological mechanisms remain ill-defined. Corticotropin-releasing factor (CRF)-expressing neurons in the bed nuclei of the stria terminalis (BNST) are involved in anxiety and stress responses, and they play a major role in the withdrawal. A subcommissural population of CRF neurons in the BNST (vBNSTCRF) is heavily innervated by hindbrain noradrenergic neurons that co-express prolactin releasing peptide (PrRP). Because these PrRP neurons are sensitive to both stress and interoceptive state, they are likely involved in the development of stress hypersensitivity following withdrawal. However, the role of PrRP neurons in alcohol-related behaviors has not been studied. I hypothesize that signaling of PrRP neurons to vBNST during acute ethanol withdrawal contributes to the development of negative affective behaviors, and that ethanol withdrawal potentiates vBNSTCRF responses to stress and PrRP neuronal activation. In the proposed project, mice will undergo chemogenetic silencing of PrRP+ neurons projecting to vBNST during acute ethanol withdrawal to examine the necessity of the circuit in the development of negative affective behaviors (Aim 1). Then, the influence of ethanol withdrawal on in vivo calcium responses of vBNSTCRF neurons to stress and chemogenetic activation of PrRP+ neurons will be explored using fiber photometry (Aim 2). Finally, monosynaptic tracing and whole brain imaging will be used to define additional brain regions innervating vBNSTCRF neurons that may be modulated concomitantly during ethanol withdrawal (Aim 3). The results of these studies will provide an improved understanding of neurobiological mechanisms impacting affective behavioral changes during ethanol abstinence. This project also provides a strong platform to expand and strengthen the trainee’s expertise in modern behavioral neuroscience approaches, including intersectional viral strategies for chemogenetic manipulation of neural circuits, observation of cell-type specific in vivo calcium signaling, and characterization of monosynaptic inputs to specific cell populations.

Regulation of innate immunological self-tolerance, or the ability of cells to discern “self” from “non-self” has long been studied in the periphery in autoimmune disorders, especially in the context of nucleic acids (NA). Understanding of self-tolerance in the central nervous system (CNS), however, has not been thoroughly investigated despite expression of these NA-sensing TLRs by microglia, the primary phagocyte of the CNS. Published data from our lab highlights that microglia retain untranslated RNA transcripts from engulfed myelin for days after phagocytosis in vitro and in human multiple sclerosis patients. Based on these data, I hypothesized that these retained transcripts could aberrantly activate endosomal TLRs. I, thus, induced primary demyelination in UNC93B1 -/- mice, which lack functional NA-sensing TLRs, and observed that these mice remyelinate more efficiently than wildtype. These data suggest that signaling of NA-sensing TLRs suppresses remyelination during demyelinating disease. Several exciting questions have now arisen, which I will tackle in this proposal: 1) Is myelin phagocytosis causing aberrant endosomal TLR signaling? 2) Are microglia the primary cell type driving this response? 3) Does a specific NA-sensing TLR hinder remyelination? I hypothesize that TLR7 is aberrantly signaling in response to engulfed myelin RNAs in microglia and suppressing remyelination. To address these questions, I have acquired powerful in vivo molecular genetic tools to manipulate UNC93B1 and endosomal TLR function. I will first identify molecular pathways that are changed in microglia in vitro in response to chronic myelin phagocytosis and test whether these molecules are UNC93B1-dependent (Aim 1a). I will then determine if the UNC93B1 dependent effects that I observed on remyelination are microglia-specific (Aim 1b). Lastly, I will identify the endosomal TLR underlying these UNC93B1 effects (Aim 2). I am now in a strong position to molecularly dissect the role of NA sensing TLRs in remyelination during demyelinating disease, which has high long-term therapeutic potential.

B cells are essential immune cells that protect the host from infections via antibody production. This requires B cells to acquire e9ector functions and di9erentiate from naïve into germinal centers, and eventually into antibody-secreting plasma cells. Cell- cell interactions underpinning e9ective B cell response have been extensively studied, yet, less focus has been placed on soluble factors involved in this process, notably, mechanistic insights into lipid production and sensing on B cell immunity is still lacking. To this end, I will characterize the role of the liver X-receptors (LXR), nuclear hormone receptors regulating cholesterol homeostasis, during a B cell response. I aim to understand, with the highest granularity, how B cells integrate intrinsic and extrinsic lipid metabolic cues. Using cutting edge approaches, including conditional and inducible murine knock-out models, dietary interventions, targeted epigenetic profiling, single-cell RNA sequencing (ScRNAseq), and spatial transcriptomic to 1) Investigate LXR requirements for germinal center B cell and plasma cell di9erentiation, proliferation and maintenance in both homeostasis, vaccination and infection, in di9erent tissues; 2) Elucidate the molecular mechanisms of LXR transcriptional activity and regulation in germinal centers and antibody-secreting plasma cells; and 3) Identify the natural LXR ligand(s) that specifically shape B cell responses. My research will help resolve with high granularity how lipid metabolite sensing tunes humoral immunity in steady state and inflammation. Furthermore, it will help better understand B cell immuno-metabolic circuits that are tuned by lipid metabolites and that might be leveraged to design harmacological interventions enhancing antibody-mediated immunity.

Current DNP student at UMass Chan Medical School shares why they decided to pursue nursing as a career.

In today’s rapidly evolving health care landscape, the demand for highly skilled and knowledgeable nursing professionals has never been greater. As health care systems become more complex, the practice of nursing is expanding, necessitating advanced education and leadership skills to meet these new challenges. Here’s why pursuing a Master of Science for nursing interprofessional leadership is becoming increasingly important for modern nurses.

he Diversity and Inclusion Office, in collaboration with the Latino Medical Student Association, the Society for the Advancement of Chicanos/Hispanics and Native Americans in Science and Happy Feet, is planning a vibrant celebration of Hispanic Heritage Month on Thursday, Oct. 10, from 6 to 9 p.m. in the Albert Sherman Center multipurpose room. The event will honor the rich traditions and contributions of the Latinx community through an exciting evening of salsa and bachata lessons, cultural games and activities that showcase the lively spirit of Latinx culture and reflect the resilience, resistance and strength of the Latinx community. In advance of the event, read one community member’s reflection on salsa music, below.

A longtime leader in emergency medicine, David E. Wilcox, MD, FACEP, is funding a new award that will support research in the specialty at UMass Chan Medical School, where he was a valued faculty member for more than 15 years.

For Mark Eastham, MD'82, the course to a fulfilling medical career took a somewhat unusual route. It was first set on a summer day in the waters off Cape Cod, after a preliminary stop at the Hyannis Port estate of a rather well-known Massachusetts family. Many years later, the Lowell native is funding a scholarship at UMass Chan Medical School to help aspiring physicians launch their own careers in medicine.

UMass Chan Biochemistry and Molecular Biotechnology (BMB) Department newsletter for September 2024. The newsletter includes a list of new hires, upcoming events and seminars, information about this month's Anti-Racism Reading Club, department news, a link to the feature of the month, recent blog posts, a list of recent publications, wellness tips, and departmental job openings.

Leslie Shaff, MD’84, P'99, and Harvey Shaff, DMD, and their family, including David Shaff, MD’99, Heidi Shaff, MD’00, Eric Shaff, MBA, and Sharon Shaff, CPA, fund new scholarship.

This academic year, the Diversity and Inclusion Office will address the ways diversity, equity and inclusion and disability can positively intersect by focusing its speaker series, Centering the Margins, on the theme, “Advancing Accessibility and Inclusion in Health Care for People with Disabilities.” The series will kick off on Sept. 25 at noon online, with the topic “Going beyond the basics: Successful communication between health care professionals and patients who are deaf, late deafened or hard of hearing.” Members of the UMass Chan community are encouraged to attend.

Renata Silva, PhD

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Opioid overdose deaths and other substance-related mortality remain at an all-time high in the United States, and evidence suggests that mortality will continue to worsen without significant changes to the landscape of opioid use disorder (OUD) treatment. Overdose mortality is the leading cause of death in the first two weeks post-release due to a variety of factors including changes in drug tolerance during incarceration and volatility of the illicit drug supply, leading to a more than 100-fold increased risk of overdose death compared to the nonincarcerated population during this period. Despite advances in addiction health services and clinical addiction medicine, many people with OUD do not have access to healthcare or medications for opioid use disorder (MOUD) treatment, which remain the most effective treatment strategies to reduce OUD- related mortality. Correctional facilities such as jails are a critical healthcare access point for people with OUD who may not receive healthcare in other settings. However, MOUD treatment availability in jails is highly variable across the United States, leaving many people with OUD without access to evidence-based treatment while incarcerated. Implementation of MOUD treatment in jails is critical to improve accessibility of MOUD treatment and reduce OUD-related mortality in this vulnerable population. There is need for further research elucidating strategies that lead to successful and sustained implementation of MOUD in jails and other correctional settings. This proposal uses a mixed-methods approach to analyze implementation of MOUD from multiple perspectives. The proposal utilizes data from the Massachusetts Justice Community Opioid Innovation Network (MassJCOIN) study, a type 1 hybrid effectiveness-implementation study of MA Chapter 208, which established a pilot program to expand all FDA-approved forms of MOUD in MA county jails. Aim 1 will qualitatively assess organizational factors related to MOUD implementation in jails and post-release overdose risk through thematic analysis of interviews with jail staff and people who received MOUD while incarcerated in MA jails. Aim 2 will investigate the association between staff perspectives of MOUD and organizational factors such as staff training and readiness for change. Aim 3 will compare MOUD retention outcomes for people who screened positive for OUD while incarcerated between different types of MOUD treatment using the Public Health Data (PHD) Warehouse database created by the Massachusetts Department of Public Health. The proposed research and training plan will provide rigorous education in addiction health services research, which will be integrated with the robust clinical training of UMass Chan Medical School and supported through a multidisciplinary team of mentors with significant expertise in implementation science and OUD research in criminal-legal settings. This proposal will provide valuable insights into strategies that lead to effective and sustained MOUD treatment in jail settings with the goal of increasing accessibility to evidence-based MOUD treatment and reducing opioid-related mortality for people who experience incarceration.

Close to 65 million US adults have a behavioral health condition (BHC), including mental health and substance use disorders.2 Persons with BHCs have a greater burden of complex health conditions, unmet health-related social needs (HRSNs) such as nutrition insufficiency and housing insecurity, use more healthcare, and are more likely to die prematurely.2 Access to mental health, addiction treatment, primary care services, and connection to social services in the same location is uncommon, even though physical illness, unmet HRSNs, mental health disorders, and substance use disorders often co-occur.6 Fragmented care is associated with increased hospital and emergency department visits, higher complication rates, and higher episode costs.30,31 Medicaid is the primary health insurance program for underserved populations in the United States. The main objectives of many recent Medicaid behavioral health-related policy reforms have been to integrate behavioral health treatment with primary care and to connect Medicaid members with social services in primary care settings.2,4,5 6,7,8 In 2018, Massachusetts’ Medicaid program, MassHealth, launched a new Accountable Care Organization (ACO) delivery and payment system to deliver integrated person-centered care to meet members’ social, behavioral, and physical health needs by integrating care within and between healthcare and social service sectors. MassHealth’s shift to this integrated ACO model attempts to provoke improved healthcare outcomes and decreases in acute and emergency healthcare utilization for Medicaid members, typically who have a higher prevalence of complex BHCs and HRSNs than the privately insured.2,4,5 13 In this study, we will examine the effects of healthcare and social service integration on the experiences and outcomes of MassHealth members with BHCs. We will first analyze data collected from qualitative interviews among a sample of 36 MassHealth members with BHCs to identify barriers and facilitators to good health, access to care, and effective care delivery, and to characterize their experiences with the integration of social, behavioral, and physical health supports.15,16,17-21 We will then conduct a cross-sectional analysis, using survey and MassHealth administrative data from 2022, to examine the relationship between primary care providers’ perceptions of clinical and social services integration, as measured on the Provider and Staff Perceptions of Integrated Care survey, and rates of acute and emergency healthcare utilization among MassHealth members with BHCs from the same clinics.22 Finally, we will use MassHealth administrative data collected between 2020 and 2022 to quantify the effect of receiving integrated housing supports through MassHealth’s Flexible Services Program on healthcare utilization among MassHealth members with BHCs experiencing housing insecurity or homelessness.

Tailored orientations like UMass Chan’s Inclusive Excellence Orientation, held for students historically underrepresented in medicine, are necessary because they remind students that they belong and gives them an opportunity to meet people who will be part of their network and sphere of influence.

Applying to nursing school can be an exciting and daunting process. Here are five tips to help you succeed in your nursing school application.

UMass Chan Biochemistry and Molecular Biotechnology (BMB) Department newsletter for August 2024. The newsletter includes a list of new hires, upcoming events and seminars, information about this month's Anti-Racism Reading Club, department news, a link to the feature of the month, recent blog posts, a list of recent publications, wellness tips, and departmental job openings

Meet this month's feature, Joshua Pajak from the Kelch Lab in the BMB Department!

Join us (the BMB) in celebrating RNA Day by learning more about the innovative bioengineering by the Pederson Lab.

During this collaborative, she and her team worked with 10 community health centers to facilitate the implementation of a patient-centered approach to social needs screening. The approach, which they developed based on motivational interviewing, trauma-informed care, and stakeholder input, was called empathic inquiry.

Discussing Kim Kardashian's son's vitiligo diagnosis, dispelling myths, and raising awareness for a better future. Learn more and get support.

Vitiligo representation is growing in toys! Dolls, video games, and more now feature vitiligo. This promotes acceptance and understanding of vitiligo.

UMass Chan Biochemistry and Molecular Biotechnology (BMB) Department newsletter for July 2024. The newsletter includes a list of new hires, upcoming events and seminars, information about this month's Anti-Racism Reading Club, department news, a link to the feature of the month, recent blog posts, a list of recent publications, wellness tips, and departmental job openings.

Learn why sun protection is vital for connective tissue disorders & get sun safety tips

Dermatomyositis explained: Muscle & skin disorder. Causes, treatments & living well.

Meet our feature of the month, research associate Hannah Brown of the Ryder Lab!

Pride is a vibrant and empowering celebration of diversity, inclusion and acceptance. However, we gather today at a time of both celebration and deep concern. While Pride serves as a powerful reminder of the LGBTQ+ community’s achievements and resilience, it also highlights the ongoing struggles they face

World Vitiligo Day, June 25th, is a day to raise awareness about the vitiligo, advocate for people with it, and foster a strong sense of community.

Vitiligo understanding & support. Learn about vitiligo & how to show support on World Vitiligo Day.

JAK inhibitors are a medications that show promise in treating vitiligo by interrupting the immune system signals that attack melanocytes.

UMass Chan Biochemistry and Molecular Biotechnology (BMB) Department newsletter for June, 2024. The newsletter includes a list of new hires, upcoming events and seminars, information about this month's Anti-Racism Reading Club, department news, a link to the feature of the month, recent blog posts, a list of recent publications, wellness tips, and departmental job openings.

A table header cell should have the role of columnheader or rowheader as this describes its relationship to other cells in the table. Learn how to fix this issue.

Meet the feature of the month, Jessica Chrabasz! Jessica is a research associate in the Pryciak Lab and Massachusetts native. Find out more about the unique perspective she brings to the BMB department.

2024 Annual Lupus Symposium

The FDA recently announced the approval of Cosentyx for the treatment of hidradenitis suppurativa in adults

Recent Hidradenitis Suppurativa research suggests a potential new therapy in the fight against this condition using Botox