Brigham And Women'S Hospital

NIH Research Projects · FY 2024 · 2024-06

ABSTRACT This conference grant application requests funds to help support the 2024 International Conference on EBV & KSHV. The conference will be held at the Boston Park Plaza Hotel. This joint conference is unique and innovative in that it combines the International Workshop on Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) and Related Agents and the International Symposium on Epstein-Barr Virus (EBV) and Associated Diseases. The funds will be used to reduce the conference registration costs for outstanding pre- and post- doctoral trainees, historically under-represented minorities including those from underserved areas. The goals of these meetings are consistent with the mission statements of the NIH, NCI, NIAID, and NIDCR, namely, to advance and promote the pace of research on infections associated with human cancer and other diseases, including in the setting of HIV-AIDS. The joint EBV & KSHV Meeting will be held June 29th – July 3rd, 2024. All remaining costs for these conferences will be raised from registration fees paid by the conferees and contributions, foundations, and pharmaceutical and biotechnology companies. The main focus of the EBV & KSHV meeting is on the biology of oncogenic herpesviruses and associated human diseases, with specific emphasis on viral pathogenesis, viral latency and reactivation, viral gene expression and replication, host responses to infection and autoimmunity, epidemiology, vaccine development, and therapeutic intervention. In addition to EBV and KSHV, studies related to Herpesvirus saimiri, murine herpesvirus-68, rhesus rhadinovirus, and rhesus lymphocryptovirus will be presented. The combined EBV/KSHV conference has not been held since 2018 and will optimize the potential for synergistic interactions among the conferees and the potential for new collaborations.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Immunotherapy holds the promise of a cure for cancer. However, only a subset (<20%) of patients exhibit durable response to immunotherapy. This is because immune checkpoint inhibitors need immune cells in the tumor. However, many tumors are found to be immunologically barren or cold, i.e. lack tumor infiltrating lymphocytes (TILs). Overcoming this barrier is key to a cure for cancer. We recently discovered that cancer cells form physical nanoscale tentacles (tunneling nanotubes) to connect with and harvest mitochondria from immune cells, which depletes the immune cells. Recent evidence show mitochondria-harvesting tumors have poor clinical outcomes. There is is an unmet need to target this novel mechanism of immune evasion. There are two distinct and complementary strategies to achieve this goal: (1) Engineer CAR-Ts or TILS with extra mitochondria (augmented T cells) such that any loss of mitochondria to cancer cells doesn’t not fully deplete the immune cells of their metabolic capacity; and (2) Disable the ability of a cancer cell to form nanotubes to harvest immune cell mitochondria. In this proposal, we aim to develop an immunotherapeutic regimen that combines these two strategies with an immune checkpoint inhibition. Specifically, We will evaluate different organelle transplantation technologies for delivering mitochondria, a nanoscale structure, to a T cell ex vivo prior to infusion as cell therapy (Aim 1); (2) Test the antitumor efficacy of these mitochondria-augmented T cells in combination with a drug that inhibits the capability of cancer cells to form nanotubes and an immune checkpoint inhibitor (Aim 2); and Dissect the mechanisms underlying mitochondrial harvesting (Aim 3). These studies can lead to paradigm shift in immunotherapy and generate fundamental insights into cancer-immune cell communications at the nanoscale.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY Accumulating evidence supports that B cell can regulate immune responses and are essential for limiting inflammation and autoimmunity by IL-10-dependent and -independent mechanisms. The processes and mechanisms by which B cells with regulatory properties are generated have also not been identified. We have shown that Tim-1 is also expressed on B cells that produce IL-10 and Tim-1 is required for apoptotic cell (AC) binding to B cells and induction of IL-10. We generated a mouse with a conditional deletion of Tim-1 selectively on B cells (Tim-1BKO). The Tim-1BKO mice show progressive loss of IL-10 production in B cells and, with age, developed severe multi-organ tissue inflammation including colitis, dermatitis, hepatitis and a paralytic disease with meningeal inflammation in the CNS. On the other hand, Tim-1BKO mice show strong anti-tumor immunity with inhibition of tumor growth. Therefore, in addition to serving as a marker for regulatory function of B cells, Tim-1 as a phosphatidylserine receptor is also functionally required for optimal regulatory B cell function. However, it is not clear what induces Tim-1 expression and what are the transcription factors that drive Tim-1 expression and regulatory B cell function. Our data clearly shows that Tim-1 does not define a subset of B cells but can be induced on B cell upon activation. Based on the preliminary data we hypothesize that Tim-1 is a functional marker on B cells that can induce IL-10 upon binding to AC and regulate tissue inflammation, autoimmunity, and anti-tumor immunity. To address this hypothesis we propose to: 1) Identify Transcriptional Regulators of Tim-1+ B cells, focusing on EHF as the positive regulator of Tim-1, which was identified by a focused Crispr-Cas9 screen; 2) Study the effect of loss of Tim-1 on B cells in generating pro-inflammatory effector B cells, as Tim-1BKO B cells are highly activated and produce proinflammatory cytokines including IL-23 and IL-6 which promote differentiation of pathogenic Th17 cells; 3) Study the role of Tim-1+ B cells in maintaining stem-like Th17 cells and limit differentiation of pathogenic CXCR6+ Th17 cells. We have found that Tim-1+ B cells produce Wnt10a, which promotes stemness, and other suppressive cytokines that keep Th17 cells in a stem-like state and limit their differentiation into pathogenic Th17 cells. The proposed studies will greatly increase our understanding of the role of Tim-1 in B cells and the generation of regulatory activity on B cells to promote immune tolerance and limit tissue inflammation and autoimmunity. These studies will provide a novel therapeutic strategy by targeting B cells for the treatment of autoimmune diseases and promoting anti-tumor immunity.

NIH Research Projects · FY 2026 · 2024-06

Every year ~100,000 young people in the US develop a first episode of psychosis and more than one million have attenuated psychotic symptoms such as problems in perception, thinking and communication, which are suggestive of a clinical high risk (CHR) for psychosis. These symptoms appear during critical periods in brain development and have important ramifications for current and future function and morbidity. Of note, prior clinical trials have not been successful in preventing psychosis onset, or other non-psychosis outcomes. There are many reasons why. One is that clinical trials have been small, which is especially problematic given that attenuated symptoms are heterogeneous, and stratification into meaningful subgroups requires large samples. Another issue is that most clinical trials have not been mechanistic, due to a dearth of validated and robust biomarkers for psychosis risk, and for other clinically important outcomes, such as mood and substance disorders, suicidal ideation and behavior, persistent motivational/hedonic deficits and further functional decline. Prior investigations have also not included standardized data protocols across studies. In response to these challenges, in 2020, the NIMH launched the Accelerated Medicines Partnership® Schizophrenia (AMP® SCZ) project, a large, observational study designed to de-risk the drug development process through validation of drug development tools, including biomarkers related to cognition, brain structure and function, fluid biomarkers, genetic vulnerability and communication. Investigators in the current proposal led the Data Processing, Analysis and Coordination Center (DPACC) for the AMP SCZ project to manage and coordinate data from the clinical networks, overseeing all aspects of data flow, quality assurance, processing, and analysis. The current proposal is in response to RFA-MH-24-151, the next phase of the AMP SCZ project, to perform Proof of Principle (PoP) clinical trials utilizing Phase 2 ready compounds to target pathophysiologically relevant mechanisms that have the potential to produce a detectable signal (change) in biological, digital, cognitive, or clinical outcome measures within a 12-16 week period of study. We propose the Clinical Trial DPACC (CT-DPACC) to provide executive management, direction, and overall coordination, including data processing and analyses of data for the PoP trial(s). We will maintain the current research team and organizational structure and augment it with a strong regulatory team, including a contract research organization, to support investigational new drug submission(s) and perform regulatory and safety monitoring. Our specific goals are (1) offer study design and regulatory support, (2) manage, direct, monitor, and coordinate the multi-site clinical trials, and (3) develop data operation procedures, biostatistics, and data analysis. Successful completion of the CT-DPACC project, in conjunction with the supported PoP clinical trials network, is expected to yield clinically validated compounds for CHR.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY/ ABSTRACT Identifying mechanistic pathways underlying Alzheimer's Disease/Alzheimer's Disease-Related Dementias (AD/ADRD) is critical to discovering new targets to test for preventive and therapeutic interventions. Metabolic dysregulation, both systemic (e.g., diabetes) and cerebral (e.g., dysfunctional lipid/insulin signaling), is associated with higher dementia risk and AD-related neuropathology. Growing evidence from genetic and molecular research, and initial studies of metabolomic profiling in postmortem brain tissue, collectively indicate that metabolic mechanisms may underlie AD/ADRD. However, the specific brain metabolic pathways involved in AD/ADRD are not well-understood; and critical research gaps remain. First, existing metabolomic studies in brain tissue – the target organ of dementia – have modest sample sizes and limited replication. Second, deeper interrogation is needed for brain biochemicals that appear related to brain function (e.g., complex lipids and fatty acids, lipid mediators of inflammation, gut microbiome-related neurochemicals, glucose/bioenergetic metabolites). Finally, the plausible causal role of brain metabolic regulation in dementia is yet to be explored. The overarching goal of this proposal is to comprehensively examine brain metabolites associated with cognitive decline. Specifically, we will use clinical, neuropathologic, and genomic data, as well as postmortem brain tissue from 1,200 deceased individuals from two community-based aging cohorts – the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). For the proposed research, we will leverage existing brain metabolomic data in ROSMAP, and strategically generate new data by extending the sample size as well as metabolites profiled -- allowing us to examine a total of ~1,800 metabolites across three platforms. In Aim 1, we will use agnostic discovery to identify and then independently replicate metabolites and metabolomic coregulatory networks associated with cognitive decline; and we will integrate genetic data using Mendelian randomization analyses to infer plausible causality. In addition, as a novel approach to discovery, in Aim 2, we will anchor discovery to a metabolic risk factor for dementia. Specifically, diet is integral to metabolism, and healthy dietary patterns are associated with slower cognitive decline and lower dementia risk; thus, we will identify brain metabolomic profiles associated with healthy dietary pattern in MAP, and then test these profiles in relation to cognitive decline in ROS. We have successfully utilized such approaches in our prior work. Finally, in the exploratory Aim 3, we will identify metabolomic profiles associated with cognitive resilience (the ability to maintain cognition despite the presence of neuropathology). IMPACT: Led by an Early- Stage Investigator and supported by an interdisciplinary team of experienced researchers, this proposal is poised to discover novel brain metabolic pathways associated with cognitive health, and provide new evidence that may inform novel interventions. In addition, we will generate extensive brain metabolomics data to share with the scientific community, yielding a significant and sustained impact on the field.

NIH Research Projects · FY 2025 · 2024-06

Abstract We pioneered a novel regulatory CD8 T subset (CD8 Treg) that promotes transplant tolerance by suppressing pathogenic CD4 T cells. CD8 Tregs use semi-variant TCRs that allow the selective killing of alloreactive CD4 T cells via recognizing the surface class-Ib MHC molecules (Qa-1 in mice and HLA-E in humans). These CD8 Tregs express distinctive co-signaling receptors, including inhibitory Killer Ig-like receptor (iKIR), a checkpoint that constrains the uncontrolled response of CD8 Tregs. The overall goal of this project is to leverage the expertise we gained through the study of mice CD8 Tregs to develop clinically relevant CD8 Treg immunotherapy. Our central hypothesis is that HLA-E-binding superagonists and iKIR inhibitors can selectively mobilize human CD8 Tregs and promote allograft tolerance. In Aim 1, I will exploit the semi- variant nature of HLA-E-restricted TCRs to develop a tolerogenic superagonist that specifically stimulates CD8 Tregs. This will be achieved by defining a dominant TCR used by human CD8 Tregs and reconstructing this TCR to screen for a potent inducer from a peptide-HLA-E presenting yeast library. Using a kidney transplant recipient's PBMCs, I will validate the efficacy of selected superagonists inducing CD8 Treg cytotoxicity against alloreactive CD4 T cells. In Aim 2, I will study the mechanism of iKIR controlling the CD8 Treg response. I will analyze the phosphorylation status of TCR signaling molecules and examine the change in CD8 Treg effector capacity upon blocking the iKIR, in vitro. To investigate the role of iKIR expressed by human CD8 Tregs in vivo, I will use a novel humanized kidney organoid transplant model we established; I will analyze the activation of CD8 Tregs, suppression of alloreactive CD4 T cells, and prolongation of kidney organoid allograft survival when humanized hosts are treated with an iKIR-inhibiting antibody. Successful completion of the project can transform therapeutic strategies to achieve tolerance by suggesting a human CD8 Treg vaccine, CD8 Treg-specific checkpoints, and a novel humanized mice model that allows studying CD8 Treg immunotherapy, in vivo. The K08 award is necessary and sufficient to advance my niche in catalyzing preclinical discoveries into phase-1 trials and to pursue my long-term goal of developing clinically relevant personalized tolerogenic therapies.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY (See instructions): Research on environmental risk factors for autism spectrum disorder (ASD) has overwhelmingly focused on maternal gestational exposures and early postnatal environments, while the potential etiologic contribution of paternal preconception factors remains largely unexplored. Yet robust and consistent associations between paternal age and ASD suggest that paternal factors may play a meaningful biological role in ASD etiology. Growing evidence also indicates that air pollution, inflammatory and metabolic comorbidities, and certain medications can affect sperm quality and induce epigenetic alterations with potential consequences for offspring neurodevelopment. These findings point to the paternal preconception period, and specifically the spermatogenesis window, as a critical and potentially modifiable period through which environmental and clinical exposures may influence ASD risk. The objective of this proposal is to investigate the role of the paternal exposome in ASD etiology. Specifically, I will: (Aim 1) evaluate whether paternal exposure to fine particulate matter (PM.) and gaseous pollutants during spermatogenesis is associated with ASD risk, quantifying both mixture-level and onstituent-specific contributions; (Aim 2) assess the associations between paternal comorbidities, related pharmacologic treatments, and ASD risk; and (Aim 3) characterize crossdomain interactions between air pollution exposures, comorbidities, and medication use to identify exposomedefined paternal subgroups with heightened vulnerability. To achieve these aims, I will leverage two complementary, large-scale U.S. administrative claims datasets, Medicaid and MarketScan, containing over 1.5 million pregnancies linked to both parents. These data provide detailed longitudinal information on diagnoses, procedures, and medication dispensing, along with the population diversity needed to evaluate heterogeneous susceptibility. High-resolution air pollution exposure estimates will be derived using advanced spatiotemporal models capable of resolving total PM mass, specific PM. constituents, and traffic-related gases at a 100-meter resolution across the contiguous United States. By integrating environmental exposures with clinical and pharmaceutical factors, this research will make novel contributions to understanding paternal pathways influencing ASD risk. The work will identify specific paternal risk profiles and potential toxic synergies, generate new evidence on modifiable preconception exposures, and lay the foundation for targeted prevention strategies within the emerging field of precision environmental health. It will also advance methodological approaches for mixture modeling in high-dimensional heterogeneous

NIH Research Projects · FY 2024 · 2024-06

Project Summary Clostridioides difficile (CD) is a ubiquitous, spore-former and the most prevalent healthcare- associated infection. While infections are often triggered by antibiotics, particularly in immunocompromised individuals, we know little about the factors and risks for triggering symptomatic CD infection (CDI). The overarching objective of Dr. Cersosimo’s research is to understand the dynamics of CDI in at-risk patient populations and optimize testing strategies for toxin C. difficile carriage to enable surveillance in broad clinical settings. The proposed research uses advanced genomic-epidemiologic analyses to enhance our understanding of CDI epidemiology in at-risk inpatients, identifies associations among C. difficile genomic and antibiotic resistance profiles, and optimizes current hospital CD surveillance programs for deployment to a diverse range of healthcare institutions. Aim 1 applies molecular epidemiologic strategies to identify patient and strain-specific risks for the development of CDI. Subaim 1a defines the dynamics of infection risk in oncology and ICU wards with genomic-epidemiologic analyses of CD in patients and using patient co-variate data obtained from the electronic health record. Subaim 1b defines genomic and phenotypic drivers of strain antibiotic resistance and their contribution to asymptomatic carriage and progression to CDI in inpatient oncology wards versus other ICU settings. Aim 2 optimizes tools for CD surveillance through the a) development of a more rapid and accessible clinical diagnostics assay for the identification of toxin positive CD and b) generation of informative data that demonstrates antibiotic triggers of CD carriage to inform population-based CDI preventative strategies in collaborations with clinical infection control and infectious disease pharmacy teams. Dr. Cersosimo brings a One Health background per her previous training in animal gut health, clinical diagnostics, and food science. Her prior experiences and training goals will: 1) optimize bioinformatic and statistical approaches in the analysis of C. difficile genomic data, 2) advance her understanding of microbiology, infectious diseases, epidemiology through hands-on learning in the healthcare setting, 3) develop strategies to generate, analyze, and interpret high-dimensional genomic and phenotypic antibiotic resistance data to inform strain genomic landscapes and associated hospital-focused antibiograms for C. difficile, and 4) improve her professional and leadership skills to progress as an independent investigator studying questions in infectious disease genomics and epidemiology from a One Health perspective. Her appointments at Brigham and Women’s Hospital and Harvard Medical School provide access to state-of-the-art clinical, laboratory, and computational resources and an internationally renowned mentoring committee with expertise in C. difficile epidemiology, antibiotic stewardship, genomics, and hospital infection surveillance. Educational resources in infectious disease epidemiology, advanced biostatistics, and clinical microbiology will further enable her training goals and career progression to independence.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY: The nasal mucosa consists of two distinct compartments - olfactory neuroepithelium and respiratory epithelium. As such, the nose serves as both a respiratory and as a sensory organ. Among the epithelial cells strategically positioned at the apical surface at the site of interaction with the inhaled air in the olfactory and respiratory epithelium are two populations of specialized cells with shared core mediator profile but distinct receptor repertoire – the olfactory TRPM5+ microvillous cells (MVCs) and the respiratory solitary chemosensory cells (SCCs). While bitter taste receptors, bitter tasting bacterial metabolites and succinate are well defined ligands of respiratory tuft cells (tracheal brush and respiratory SCCs), the ligands and signaling pathways of olfactory TRPM5+ MVCs are less well defined. We recently found that TRPM5+ MVCs detect allergens and the danger signal ATP to generate proinflammatory mediators including cysteinyl leukotrienes and prostaglandins in an in vitro system. We also demonstrated that allergen recognition by the olfactory TRPM5+ MVCs initiates an aberrant response of stem cell proliferation in the absence of profound inflammation in the olfactory mucosa. Here, we will determine how the TRPM5+ MVCs contribute to the integrated airway epithelial response to allergens and the determinants of pro- vs anti-inflammatory programs directed by these new members of the tuft cell family. In Aim 1, we will define the signaling components engaged upon allergen detection by TRPM5+ MVCs. In Aim 2, we will determine how signals detected by TRPM5+ MVCs are propagated in the olfactory neuroepithelium, and the mediators (eicosanoids, epithelial cytokines, acetylcholine) generated by TRPM5+ MVCs or immediately downstream of them. Findings here will clarify how the olfactory TRPM5+ MVC tuft cells detect allergens, the consequences of their activation, and possible therapeutic targets.

NIH Research Projects · FY 2026 · 2024-06

Establishing mechanism-based therapeutics for Parkinson’s disease (PD), Lewy body dementia (LBD) and other synucleinopathies is a biomedical priority. Neuropathological and genetic discoveries implicate α-synuclein (αS) in familial and ‘sporadic’ PD. Recent publications identify significant lipid components with misfolded αS in Lewy bodies and Lewy neurites, transforming how we conceptualize PD pathogenesis, as lipids are central to many fundamental cellular processes and are highly abundant in the brain. αS has physiologic and pathogenic interactions with phospholipid membranes and fatty acids (FAs) and alters lipid homeostasis. Here, we propose in vitro and in vivo approaches to dissect the interplay of αS with lipid membranes. Experiments are focused on advancing PD-dysregulated LIPE (hormone sensitive lipase) as a candidate therapeutic target for PD/LBD in vivo and establishing the mechanism of rescue centered on αS:lipid membrane interactions at the synapse. We posit a dynamic relationship between normal and pathological forms of αS and FAs. Our central hypothesis is that αS dyshomeostasis results in cellular FA metabolism imbalance, altering αS:membrane interactions and disease phenotypes. This hypothesis underpins the PI’s central goal in this R01: to return the abnormal disease- associated cellular lipid/FA content to equilibrium in several compelling cellular and in vivo models of PD and LBD. This proposal has 2 distinct Aims focused on advancing monounsaturated FA therapeutic strategies, addressing mechanistic and therapeutic questions. 1. We propose a mechanistic dissection of αS:membrane interactions at the synapse, investigating disease-associated synaptic vesicle abnormalities, αS aggregation, and the role of membrane FA composition in disease phenotype rescue. 2. We propose to evaluate LIPE as a therapeutic target for reversal of motor deficits and αS neuropathology with detailed genetic, biochemical, and pharmacological analyses in multiple mouse PD/LBD/synucleinopathy models. The PI has already reported a FA target for PD, SCD inhibition, now in human PD clinical trials. Additionally, the PI has published data generated in support of this proposal in patient-derived neurons identifying LIPE (a functionally distinct, innovative target) as a candidate PD/LBD therapeutic target. These 2 distinct but complementary Aims should advance mechanistic understanding of αS:membrane interactions and progress a candidate therapeutic target (LIPE) for lipid dysfunction in PD and LBD.

NIH Research Projects · FY 2025 · 2024-06

Background: Sex has a profound effect on cardiovascular disease (CVD) occurrence and associated risk factors. Our research group, and others, have characterized metabolomic profiles associated with CVD. However, no studies have comprehensively examined the impact of sex on the metabolome and how these differences contribute to differences in CVD risk. These analyses may offer clues about sex differences in the biologic pathways related to CVD. Goal: We will examine the impact of sex on the metabolome, generate sex-specific metabolomic signatures, and evaluate their contribution to CVD risk in women and men across generations. Setting: We have assembled an exceptional team with deep expertise in women's health, cardiovascular disease, metabolomics, and biostatistics/bioinformatics. Research Plan: Our aims leverage four large, unique cohorts: (1) the UK Biobank (UKB; N=502,386 men and women, N=274,236 with metabolomics); (2) COMETS consortium (N=130,000+ men and women) (3) the Women's Health Initiative (WHI-CHD; N=2306 women with metabolomics in a CHD case-control study); and (4) Nurses' Health Studies (NHS-Stroke, N=908 women with metabolomics in a stroke case-control study). Aim 1 will use the UK Biobank (UKB, n=274,236 with metabolomics) to derive two signatures: (a) a sex metabolite score (UKB-SMS) and (b) a sex metabolite class score (UKB-SMCS). These scores will quantify molecular differences between women and men and assess which factors (eg. hormonal exposures, adiposity, etc.) partially account for them. We will then test the associations of UKB-SMS and UKB-SMCS with incident CVD, coronary heart disease (CHD), and stroke, separately in men and women and across generations. Aim 2 will extend this work to the international COMETS consortium (N=130,000+) using comprehensive metabolomic platforms. We will (a) derive a COMETS-based sex metabolite score (COM-SMS), (b) test associations of COM-SMS with incident CHD in the WHI-CHD (N=2306) and stroke in NHS-Stroke (N=908), and (c) evaluate the association of the UKB-SMCS with incident CHD and stroke in WHI-CHD and NHS-Stroke, respectively, to determine the generalizability of sex-specific metabolomic signatures across populations. Aim 3 will identify CVD-related metabolite signatures separately in men and women within UKB (N=274,236). We will develop CVD metabolite scores (CVD-MS) and metabolite class scores (CVD-MCS), compare their associations with CVD across sexes, and conduct network analyses to map shared versus sexually dimorphic pathways underlying CVD, highlighting sex-specific biological processes that may serve as novel therapeutic/preventive targets.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY/ABSTRACT: Recent FDA accelerated approvals of two anti-amyloid antibody treatments, aducanumab and lecanemab, for early-stage Alzheimer’s disease (AD) provide the first disease-modifying treatments to date, albeit with modest- to-moderate slowing of cognitive decline, and potentially fatal vascular side effects known as Amyloid Related Imaging Abnormalities due to edema (ARIA-E) or microhemorrhages (ARIA-H) in a subset of patients, especially ApoE4 carriers. A recent press release reported efficacy and ARIA in a Phase 3 trial of donanemab, another antibody targeting aggregated amyloid- (A) protein. ARIA is mostly asymptomatic and transient but occasionally causes more severe cortical edema and hemorrhage, which makes understanding and mitigating ARIA an urgent unmet need as these antibodies move into the clinic. Strong but circumstantial evidence points to cerebral amyloid angiopathy (CAA), Aβ deposits within the brain vasculature, rather than amyloid plaques, as a cause of ARIA. Patients with CAA in addition to amyloid plaques are at higher risk of ARIA than patients with plaques but no CAA. Patients carrying an APOE ε4 allele, which predisposes to CAA and impairs Aβ clearance across the blood-brain barrier, are also at higher risk than patients with ε3 or ε2 alleles. We hypothesize that infused anti-amyloid antibodies first encounter and bind vascular amyloid and cause ARIA. Testing this hypothesis requires determining if antibodies that cause more ARIA (e.g., aducanemab) bind more vascular A, localize earlier and at higher concentrations to vascular A, and cause more immune activation toward vascular A than antibodies that cause less ARIA (e.g., lecanemab). APOE is likely to play a role as an anti-APOE antibody, HAE-4, has been reported to clear both vascular and plaque amyloid while restoring vascular function (Xiong et al., 2021). Complement fixation of the anti-A antibodies at sites of vascular amyloid may lead to activation of the complement cascade that results in a proinflammatory response, BBB leakage, edema and microhemorrhage. Therefore, we hypothesize that combining anti-amyloid antibodies with antibodies targeting poorly lipidated APOE associated with fibrillar amyloid or complement C1s to block complement activation will mitigate ARIA and perhaps improve efficacy. We propose the following three Aims: 1. We will compare four anti-amyloid antibodies (aducanemab, lecanemab, gantenerumab and donanemab) for their binding to plaque vs. vascular amyloid both biochemically and pathologically. 2. We will define the timing of ARIA and characterize vascular changes after 2, 4 and 8 weekly treatments with recombinant murine aducanemab, lecanemab and donanemab in aged 5XE4 mice. 3. We will combine the anti-amyloid antibody most prone to induce ARIA in Aim 2 with the HAE-4 anti-APOE antibody or an anti-C1s antibody to block the activation of the classical complement pathway to mitigate ARIA in aged 5XE4 mice. If successful, we will have a mechanism for anti- amyloid immunotherapy-related ARIA. Combination trials targeting amyloid and APOE or C1s in humans could be initiated to improve the efficacy and safety of anti-amyloid antibody immunotherapy.

NIH Research Projects · FY 2026 · 2024-06

SUMMARY Dynamics of interorgan communication and biological age change as a function of chronological age but these dynamics and the underlying mechanisms are not well understood. Organ transplantation offers a clinically most relevant model with donor/recipient age-discrepant combinations representing a clinical routine to meet the ever- increasing organ demands. Our published studies and preliminary data show that an elevated donor age drives the immunogenicity of organs leading to augmented alloimmune responses with higher acute rejection rates. This, in turn, is blunted with the increase of recipient age, demonstrating both clinical relevance and inter- organ/recipient communication. These clinically relevant scenarios raise the possibility of potential rejuvenation and/or accelerated aging when performing heterochronic organ transplants. We have shown that the recipient environment can affect the biological age of transplanted organs. Specifically, when transplanting old organs in young recipients, we observed the reduction of donor organ biological age. At the same time, old organs transplanted into young recipient mice promoted aging, which not only led to an accumulation of senescent cells in peripheral organs, but also to a decline of physical and cognitive functions. Our project brings together a synergistically positioned group of aging and transplantation researchers and clinicians. Vadim Gladyshev (MPI) is an expert on aging biomarkers and the biology of aging. Stefan Tullius (MPI) is a clinician/scientist who provides the clinical perspective. The latest generation of aging biomarkers based on omics approaches, combined with state-of-the-art model systems place us in an unprecedented position to study inter-organ dynamics of aging. Our hypothesis is that that young and old cells transferred with an organ transplant may exert rejuvenating and aging effects extrinsically. This hypothesis will be tested in our established transplant models of clinical relevance and confirmed using a unique clinical database. We also hypothesize that transplanted organs will acquire the biological age approaching that of recipients. This includes the situation wherein old donor organs will be rejuvenated in young recipients, potentially increasing the use of discarded organs. This approach is significant and innovative in (i) delineating novel mechanisms of interorgan communication in a clinically relevant heterochronic transplantation model with perturbation of specific tissues, (ii) the use of state-of-the-art tools of aging science to characterize changes in biological age dynamics, (iii) the use of detailed mechanistic approaches to pinpoint changes in interorgan communication upon biological age perturbation; (iv) synergistic efforts of research groups combining deep complementary expertise in preclinical and clinical studies of aging biology and transplant medicine; and (v) real-world implications of the proposed work. These studies position us to substantially advance understanding of interorgan communication with regard to biological age, with the potential to delineate novel pathways in support of organ rejuvenation and the prevention of transferring age- accelerating effects with organ transplantation.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY Congenital heart disease (CHD) is the most common human birth defect and occurs in ~0.8% of live births. CHD has a known genetic etiology in approximately 45% of cases. Whole exome (WES) or genome (WGS) sequencing of 9072 CHD probands by the Pediatric Cardiovascular Genetics Consortium (PCGC) has identified a significant burden of damaging protein-coding variants in 269 genes (denoted CHD genes). Although WES analyses of the full PCGC cohort (17,000 probands) is ongoing, the predicted functions of these CHD genes indicate that CHD often arises from dysregulated expression of cardiac developmental genes. Within the ~55% of CHD cases with unknown etiologies (denoted WES-negative), CHD genes harbor many rare missense, splice site-associated, and noncoding variants with unknown pathogenicity. Here we test the hypothesis that de novo and rare variants of unknown significance (VUSs) in non-coding and coding regions are responsible for a subset of CHD that remains unexplained. Non-coding de novo VUS (ncDNV) identified in proximity to genes that impact heart development will be studied in massively parallel reporter assays to determine if they impact cis-regulatory element activity in cardiac lineages differentiated from iPSCs. Candidates will be further studied by introduction into the endogenous locus and impact on gene expression and cell transcriptional states will be assessed by single nucleus RNA sequencing (snRNAseq). Concurrently we will study coding region VUS in two ways. Using CLINVAR assignment of pathogenicity and AlphaMissense, a deep learning model built on protein structure that variant effects, we will prioritize rare missense VUS for introduction into iPSCs and cardiac lineages. Using snRNAseq we will compare missense VUS to reference and loss of function variants. Additionally, we will interrogate splice site-associated VUS using minigene splice assays. To validate cell-based analyses we will introduce and study a selected subset of non-coding and rare missense variants in mice. With functional data on non-coding and rare missense VUS, we expect to define and characterize a subset that cause or contribute to CHD and improve predictive models of pathogenicity in genes that cause CHD and other human disorder. Identifying genetic contributors in a subset of unexplained CHD cases will improve clinical assessment of outcomes and recurrence risks and enable genotype-phenotype analyses. These insights will also advance knowledge about the mechanisms for normal cardiac development and CHD and identify patients that are appropriate for studies of non-genetic etiologies. We propose to: Aim 1. Assess the contribution of de novo noncoding VUS (ncDNV) to unexplained CHD. Aim 2. Define the contribution of rare coding region VUS in CHD genes to unexplained CHD.

NIH Research Projects · FY 2025 · 2024-06

Overview. The goal of this project is to develop a multilevel HIV prevention approach to optimize and improve how we serve those at high risk for being missed by and/or falling off the HIV prevention cascade - people who use drugs (PWUD) who also belong to other key HIV risk groups (transgender women, men who have sex with men [MSM], Black/Latinx/Indigenous people). Specifically, the study will develop mSYNC, an mHealth SYNdemic-based, C&L psychology HIV prevention intervention for the emergency department (ED). Significance. Despite efficacious interventions for HIV, services are not reaching minoritized PWUD who continue to have high incidence. Syndemic theory proposes that co-occurring, mutually reinforcing psychosocial challenges (drug use, mental health, minority stress, unmet basic needs) drive HIV risk behavior and create barriers to care access. Alternative prevention efforts are needed to address this holistic syndemic HIV risk profile among minoritized PWUD and overcome historical barriers to reach. Due to low engagement in regular clinic-based care, minoritized PWUD have high utilization of drop-in care via EDs. With long wait times, ED visits are a prime opportunity to engage minoritized PWUD we are not reaching. Consultation-liaison (C&L) psychology offers a compelling framework to deliver a syndemic-targeted HIV intervention in the ED. Yet, EDs are overburdened with limited capacity to add services. mHealth could simulate human-delivered C&L with improvements such as continued on demand access to intervention content (individual-level intervention) and capacity build the ED to deliver integrated care for HIV prevention (hospital-level intervention). Guided by the Consolidated Framework for Implementation Research, development of mSYNC is grounded in implementation science to address pragmatic barriers to uptake within complexities of EDs and lives of minoritized PWUD. Objectives/Methods. To inform implementability and create a beta version of mSYNC, an mHealth user-centered design model approach will be used (Aim 1). Aim 2 will pilot test mSYNC to assess patient-level implementation outcomes of acceptability and appropriateness via a single-arm trial with N=100 minoritized PWUD in the ED. Secondarily, change over time will be explored for HIV risk, drug use, and mental health symptoms, and linkage to care. Assessments are at baseline, post-initial app use, and 30-, 60-, and 90- day via quantitative survey and exit interview. Aim 3 will evaluate hospital-level implementation outcomes of relative advantage and compatibility via a cross-sectional survey with ED stakeholders (N=30). Innovation/Impact. Aligned with NIH high priority areas, this study capitalizes on a unique merging of disciplines to produce an innovative, real-world, low threshold approach to address HIV disparities among those at highest risk for acquisition. The potential impact is development of a scalable tool that has trans-NIH applicability to other high priority health issues disproportionately experienced by marginalized groups with broader impact for health equity. Relevant to NOT-DA-20-037.

NIH Research Projects · FY 2026 · 2024-06

Reproduction is a tightly regulated function of an organism that is crucial to the perpetuation of a species. The pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), play an essential role in the reproductive process to control fertility by directing steroidogenesis and gametogenesis. Befitting their important roles in endocrine physiology, the synthesis and secretion of LH and FSH are under complex regulation by hypothalamic neuropeptide inputs (most notably gonadotropin-releasing hormone, or GnRH) and gonadal sex steroid and peptide hormones. The precisely coordinated integration of these signals leads to appropriate LH and FSH subunit gene expression, protein synthesis, and secretion to promote sexual maturation and control normal reproductive function. With the support of this R01 award, we have identified molecular and cellular mechanisms and pathways by which these factors control gonadotropin gene expression and secretion. We have identified signaling pathways, transcription factors, and cis-regulatory elements by which varying patterns of pulsatile GnRH differentially regulate LH and FSH subunit gene expression using cellular, animal and human models. The overarching goal of this project is to delineate the mechanisms and pathways underlying the carefully orchestrated control of LH and FSH release to allow for reproductive integrity and fertility. We hypothesize that these cellular factors modulate the pathways by which varying GnRH pulse frequencies regulate gonadotropin subunit gene expression to contribute to appropriate regulation of gonadal function, cyclicity and fertility in vivo. Over the next five years, we propose to: (1) generate new mouse models to further translate our cellular studies into the in vivo context; (2) extend our studies of the downstream mechanisms by which the pulsatile GnRH signal is decoded to investigate the role of the Nr4a1 nuclear receptor family we have identified to be highly differentially regulated by varying frequencies of pulsatile GnRH; and (3) test the hypothesis that GnRHR couples differentially to G α s and G α q/11 depending on GnRHR numbers, serving as the gonadotrope GnRH pulse frequency decoder to result in subsequent differential regulation of LH and FSH. We are in a unique position to take advantage of our perifusion system combined with our molecular and cellular biology expertise in parallel with our experience in mouse genetics and physiology to successfully perform the proposed studies. The successful completion of these aims is expected to provide insight into the mechanisms by which gonadotropes decode GnRH pulse frequency to differentially regulate LH and FSH, critical for physiologic control of reproduction and fertility. The elucidation of these pathways will generate new potential therapeutic targets for treatment of infertility, precocious or delayed puberty, hypothalamic amenorrhea, and polycystic ovarian syndrome. The results obtained from this research will therefore have a significant impact on the field of reproductive medicine.

NIH Research Projects · FY 2025 · 2024-05

Project Summary/Abstract: Mast cells (MCs) expand within the airway epithelium during prevalent and burdensome human respiratory disease, including asthma and nasal polyposis, where they are thought to play a central role in disease pathobiology. The expanded intraepithelial MC compartment characteristic of Th2 high asthma correlates with disease severity and therapeutic targeting of this compartment improves patient outcomes, suggesting a central role in disease pathobiology. Despite this, the mechanism(s) through which intraepithelial mast cells participate in airway inflammation remain unclear, in part due to a lack of robust pre-clinical models to selectively target this MC subset in an in-vivo setting. This proposal describes the creation of a novel mouse strain in which tamoxifen-inducible cre recombinase coupled with a fluorescent reporter tag is selectively expressed within the lung by inflammation-expanded intraepithelial mast cells, termed mucosal mast cells (MMCs) in mice, and will use this strain to test the hypothesis that intraepithelial mast cells are an important contributor to airway inflammatory disease progression. Aim 1 of this study will validate reporter construct restriction to the MMC lineage across tissues and conduct a timecourse analysis of the dynamics of construct upregulation and its long-term maintenance within the lung MMCs compartment. Aim 2 will use our strain to generate inducible MMC knockout mice, which will then be used to test the degree to which MMC regulate pulmonary inflammation and airway hyperreactivity at two discrete phases of allergic lung inflammation. Completion of these aims will provide definitive evidence as to the importance of MMC in allergic lung inflammation and set the stage for future studies using this strain to both determine the mechanism(s) through which they influence lung inflammation and test their importance in other models of mucosal inflammation, such as food allergy and eosinophilic esophagitis.

NIH Research Projects · FY 2026 · 2024-05

Project Summary/Abstract Individuals with coexisting COPD and bronchiectasis have worse lung function, longer hospital stays, and an increased risk of death. Bronchiectasis, a pathologic airway enlargement, is increasingly recognized in the US, with 522,000 adults treated annually for bronchiectasis. Bronchiectasis is also a relevant abnormality in chronic obstructive pulmonary disease (COPD), affecting up to 72% of these individuals. While the development of advanced imaging methods has facilitated our understanding of COPD progression, a critical factor hampering our ability to examine bronchiectasis progression fully is the lack of an objective imaging tool applicable in large studies. In this proposal, we will use objective, automated, artificial intelligence-based computed tomography (CT) measures of bronchiectasis. Our overarching hypotheses are 1) our artificial intelligence-based CT measures are effective in detecting bronchiectasis changes in smoking populations and determining its clinical consequences; 2) our approach of defining proteomic biomarkers will help identify subjects at risk of structural progression, and ultimately, inform clinical care. We will quantify the extent of enlarged airways, a measure of bronchiectasis, on baseline and follow-up chest CT scans from smoking individuals participating in two well characterized cohorts, the COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). In Aim 1, we will determine the association between pulmonary vascular changes and longitudinal measures of radiographic bronchiectasis, gaining insight into pathogenesis. In Aim 2a, we will determine changes in artificial intelligence-based CT measures of bronchiectasis and their association with clinical measures of disease and lung-function trajectories; in Aim 2b, we will also determine clinical factors and imaging features associated with the development and worsening of bronchiectasis on CT. In Aim 3, we will determine blood-based proteomic biomarkers to identify bronchiectasis and its progression on CT. This study will validate the effectiveness of our new AI-based imaging tool for determining bronchiectasis progression; and proteomic biomarkers to identify subjects at risk of progression, which will inform the development of new intervention strategies.

NIH Research Projects · FY 2026 · 2024-05

Project Summary Chronic obstructive pulmonary disease (COPD) is a rising cause of mortality worldwide. Disease heterogeneity is one major barrier to understanding and therapeutic development for COPD. Understanding the molecular basis for this heterogeneity and determining the causes and consequences of the disease is a major challenge. Genetic variants, present since birth, have the potential to serve as a causal anchor for disease-related pathways and potential COPD subtypes. However, genetic variants often have small effect sizes and poorly understood functional effects. Metabolomics has emerged as a critical biomarker for lung disease but has not been assayed in lung and blood at a cohort level nor been connected to COPD genetic risk variants. In this proposal, we plan an integrative genomic approach to identify genetically driven pathways of COPD, informed by metabolomics, transcriptomics, and proteomics. First, we will curate existing and generate new genome-wide association studies for COPD-related phenotypes and implement statistical and machine learning methods to identify groups of variants displaying similar multi-phenotype association profiles. Second, to determine the molecular profiles of these groups of genetic variants, we will use existing transcriptomics, proteomics, and whole-genome sequencing data along with newly generated lung and blood metabolomics data in 1,000 subjects from the Lung Tissue Research Consortium (LTRC). We will also identify relationships between the new metabolites data, COPD and related phenotypes, and genetic variants and perform additional targeted metabolomics in 500 COPDGene subjects. Finally, we will assess the potential of these groups of variants to identify COPD subtypes, gene-environment interactions, and potential drug targets. Altogether, our integrative analysis will produce genetically informed molecular pathways and identify more specific groups of patients for therapy. In addition, genetic association, metabolomic, and methodologic resources generated for this project will be of value to the lung disease and complex trait genetics community.

NIH Research Projects · FY 2026 · 2024-05

Abstract Epstein-Barr virus (EBV) is the etiologic agent of infectious mononucleosis, is the major trigger for multiple sclerosis and is associated with a range of lymphoproliferative disorders and carcinomas. EBV is spread between hosts through the oral cavity, where it crosses epithelial barriers to infect naïve B cells in tonsil lymphoepithelial tissue. Primary EBV infection and much of the EBV lifecycle is centered in the oropharynx, which are persistently colonized. Yet, much remains to be learned about virus/host interactions that govern the oral cavity EBV lifecycle. According to the EBV germinal center model, EBV uses latency programs to navigate the B-cell compartment, initially driving B-cell activation and growth via the pre-latency, latency IIb and latency III programs. Incompletely understood cues in tonsil and related lymphoid tissues are thought to switch the EBV program to latency IIa in germinal centers. Subsequent differentiation into memory B-cells, the reservoir for lifelong EBV infection, give rise to the latency I program, comprised of a single EBV latency gene, EBNA1. However, this has remained difficult to model and limited information is available about EBV/host interactions in the tonsil microenvironment. This lifecycle is highly associated with EBV-driven malignancies, with a heavy disease burden in craniofacial regions, including Burkitt lymphoma and nasopharyngeal carcinoma. However, much remains to be learned about how EBV rewires host cell one-carbon (1C) metabolism to support key aspects of the viral lifecycle in tonsillar versus peripheral blood B-cells. We therefore used metabolomic, proteomic and CRISPR genetic approaches to identify a central role for interconnecting methionine and folate 1C metabolism pathways in support of EBV- driven B-cell transformation and the viral lifecycle. Our central hypothesis is that EBV latency programs subvert multiple levels of interconnecting methionine and folate metabolism cycles to perform non-redundant functions critical for the viral B-cell lifecycle in tonsil versus peripheral blood compartments. Using novel primary human B-cells and tonsil tissue models, our Specific Aims are therefore to: 1) Identify key mechanisms by which EBV drives newly infected tonsil and peripheral blood B-cell methionine dependency; (2) Identify key mechanisms by which methionine metabolism drives newly infected tonsil and peripheral blood Epstein-Barr nuclear antigen expression and signaling; (3) Characterize key EBV latency gene-induced methionine and folate metabolism roles in tonsil peripheral blood B-cell redox defense. Our studies will provide novel insights into crosstalk between immunometabolism, viral latency gene programs and redox defense critical for the EBV lifecycle, with relevance to novel therapeutic approaches.

NIH Research Projects · FY 2026 · 2024-05

OVERALL – SUMMARY/ABSTRACT With an ever increasing aging population and prolonged life spans, there has been a significant increase in the number of older transplant recipients. At the same time, older patients represent the fastest growing cohort waiting for a transplant. Those older patients are treated in the same way as young recipients, yet their alloimmune responses differ substantially. There is thus a significant unmet need to provide treatments for older transplant recipients that are based on a solid understanding of age-specific changes in alloimmunity. However, that cannot be done until cellular and humoral mechanisms regulating alloimmunity in aging are fully elucidated. The unmet need to conduct studies such as those proposed in this PPG is further stressed by: A) our extensive data indicating that immunoregulation controlling allo-specific responses is distinct in aging, B) that established transplant immunosuppression has been designed for a youthful immune system with an exclusion of older recipients from the vast majority of clinical studies, and C) that current immunosuppression strategies are not fully effective in older individuals and predisposes them to undesired effects. Indeed, our collected data indicate that the current aged- related immunosuppressive paradigm is overly simplistic and does not recognize important heightened inflammatory features of aging alloimmunity. Our overall hypothesis is that cellular senescence in fibroblastic reticular cells (FRCs) of lymph nodes induces a maladaptive T and B cell response leading to a dysregulated alloimmunity in aging. Clinically, this dysregulated immunity results in age-specific effects of established immunosuppressants. Co-stimulatory agents, although prime candidates for use as immunosuppression in older recipients due to the absence of nephrotoxic effects, work effectively only in young but not old recipients.. To this end, our major goals are to fully examine the cellular and molecular mechanisms that drive transplant immunity in aging. This PPG sets forth a platform that merges three highly synergistic teams (Drs. Abdi, Tullius, and Sage) with complementary skills and expertise in LN stroma, T and B cell immunity. Project 1 will test the hypothesis that aged FRCs contribute significantly to the divergent immune responses observed in aged vs. young mice. Aim 1 will study the mechanisms by which senescence in FRCs regulates alloimmunity in the LN. Aim 2 will examine the importance of lymphotoxin pathways for transplant immunity in the stroma of aged LN. Aim 3 will study novel approaches to rejuvenate the aging LN stroma thereby restoring immune tolerance following co-stimulatory blockade. Project 2 will test the hypothesis that increased age-specific changes in innate and T cell immunity rewire allorecognition, T cell metabolism, and immunosuppressive targets. As our corollary hypothesis we submit that cellular senescence augments alloimmunity and that the depletion of senescent cells improves transplant outcomes in old recipients. In Aim 1, we will delineate the mechanisms by which aged DCs regulate T-cell alloimmunity. In Aim2, we will delineate age-specific metabolic reprograming of allo-reactive T cells. In Aim3, we will test age-specific treatments of old recipients with a focus on nano-delivery of glutamine inhibitors and senolytics. Project 3 will test the hypothesis that aging causes transcriptional rewiring in Tfh and B cells altering solid organ transplant rejection. Aim 1 will determine how aging alters transcriptional rewiring in Tfh cells during antibody mediated rejection making them resistant to costimulatory blockade. Aim 2 will delineate how alterations in developmental stage progression in aging contributes to a cellular senescence-like pathogenic state in Tfh cells, and Aim 3 will determine how aged Tfh-targeted nano- therapeutics can alter allo- versus anti-viral immunity in the settings of aging. An Administrative Core (Core A), Nano-Immune Imaging Core (Core B) , and Microsurgery Transplantation Core (Core C) will provide necessary support so these three projects accomplish their goals.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY/ABSTRACT This proposal is responsive to RFA-DA-24-028, “Advancing Psychedelics Research for Treating Addiction (R01 Clinical Trial Not Allowed).” Substance use disorders (SUDs) are a public health crisis in the United States with few therapeutic options. SUDs are influenced by environmental factors including chronic exposure to psychological stress, which shares common mechanisms of neural circuit dysfunction with SUDs. For example, chronic stress disrupts mechanisms within limbic circuits controlling reward behavior, such as the nucleus accumbens (NAc) of the ventral striatum. Therefore, studying NAc circuitry in chronic stress may uncover new targets for SUDs. Psychedelics, particularly psilocybin, have emerged as powerful therapeutics to combat mood disorders and SUDs by boosting signaling via the 5-HT2A serotonin receptor. Recent work in mice has elucidated key mechanisms by which psilocybin and other psychedelics act on neurons. However, psychedelics exert effects on many cell types outside of the nervous system that express the 5-HT2A receptor, including peripheral immune cells. Yet, a key challenge in deploying psychedelics to control immune responses induced by stress is many of the immune cell types, networks, and behavioral consequences of their activity remain unknown. In preliminary studies I identified populations of peripheral immune cells that are recruited to the meninges in response to chronic psychological stress and respond to the psychedelic psilocybin through 5-HT2AR signaling. Immune cell-derived cytokines elevated in response to chronic stress decreased the expression of Inhba in NAc astrocytes, which boosted Activin A signaling in NAc neurons. In vivo genetic perturbation of Inhba in NAc astrocytes showed Inhba limits stress-induced helplessness behavior by decreasing Activin A production while Acvr2a perturbation in NAc neurons ameliorated stress-induced helplessness behavior. Psilocybin treatment ameliorated stress-induced behavioral deficits as well as immune cell recruitment by decreasing immune cell chemokine receptor and inflammatory cytokine expression, which was independent of corticosterone levels. Hence, these data suggest that psilocybin decreases pathogenic neuroimmune signals induced by chronic stress implicated in SUDs. I hypothesize that stress-induced immune cell recruitment triggers loss of Inhba expression in astrocytes, which boosts NAc neuron Activin A signaling to increase helplessness behavior. I will test this idea by: Defining the effects of psilocybin on 5-HT2A+ meningeal immune cells during chronic stress using nucleic acid cytometry (Aim 1); Determining how psilocybin-sensitive immune cells regulate astrocytes through genome- wide CRISPR screens (Aim 2); and Evaluating psilocybin-dependent 5-HT2A+ immune cell effects on reward behavior using immune cell genetic perturbations via bone marrow chimeras (Aim 3). IN SUM, this R01 tests the therapeutic potential of a psilocybin-sensitive neuroimmune circuit in chronic stress relevant for SUDs.

NIH Research Projects · FY 2026 · 2024-05

Abstract Understanding how T cell receptors (TCRs) see tumor antigens presented by MHCs is necessary to fully understand how the immune system recognizes tumor antigens, and to reap the full potential of antigen-specific immunotherapy. To achieve this goal, a quantum leap forward is required in which the revolutionary advances in machine learning are combined with a large volume of structure, function, data on matched TCR-pMHC pairs. The development of accurate predictors of TCR-antigen recognition will be dependent on the creation and integration sequencing-based datasets with high-throughput structural and functional insights. Our proposal, submitted as a CRUK/NCI Grand Challenge team (MATCHMAKERS) will combine researchers with expertise in immunology, methods development, structural biology, and computation to enable generalized prediction and design of TCR recognition. This work will be spread across four Work Packages (WPs): WP1: Large-scale generation of TCR-pMHC pairs from naturally occurring sources. We will build datasets of naturally occurring TCR-pMHC pairs. Our team will use an array of approaches to collect these datasets, from humans and from mouse models, and in the context of both cancer and immunity more generally. WP2: Ultra-high throughput TCR-pMHC matching using molecular engineering. Efforts to create general models will require a broader array of data than feasible to collect from natural TCR systems. We will use an array of synthetic approaches developed by our team to comprehensively match TCRs with pMHCs to train computational models. WP3: Large-scale structural and biochemical analyses of TCR-pMHC interactions. A key to our team’s vision is to match interaction datasets with high throughput structural and functional insights. A deep understanding of how the TCR contacts with MHC helices control function and orientation will be essential for training and testing computational models. WP4 AI-based prediction and design of TCR-pMHC interactions. We will integrate our data to train next- generation algorithms capable of generally predicting and designing TCR-pMHC interactions. These predictions will proceed through a reiterative testing and feedback circuits for further model optimization.

NIH Research Projects · FY 2026 · 2024-04

Sodium glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP- 1RA) are rapidly changing the therapeutic landscape for patients with diabetes and kidney disease, but are underutilized in high-risk populations. Randomized controlled trials (RCTs) have robustly demonstrated the cardiovascular and renoprotective benefits of these agents. For the first time in decades, we have new drugs to slow kidney disease progression, yet newer medication classes are still underprescribed in patients with DKD. One of the major prescribing barriers is the lack of safety data in real-world patients with DKD, a complex, older population with multimorbidity and polypharmacy, who are at greater risk for adverse events and drug-drug interactions (DDIs), but who are underrepresented or excluded from RCTs. This dearth of safety data cannot be addressed by RCTs, since the RCTs were powered for effectiveness, not safety, did not represent real-world patients with DKD who are an older, frailer population, and did not address DDIs in this population with a high burden of polypharmacy. Yet, over time, these drugs should and will be prescribed to a broader spectrum of patients with DKD. Methodologically rigorous studies using large, national healthcare databases are an ideal vehicle to address these knowledge gaps with much larger sample sizes than in RCTs across the broad spectrum of patients with DKD. Our overarching goal is to develop a framework to optimize the safety of newer diabetes medications in real-world patients with DKD. We will investigate kidney-related and other safety outcomes that were not systematically evaluated in RCTs in patients with DKD, using a new- user, active comparator cohort approach (Aim 1). We will develop two safety monitoring approaches to assess both anticipated and unanticipated adverse event signals associated with the newer diabetes medications as they are used in real-world patients with DKD (Aim 2). Patients with DKD are at higher risk for DDIs since they are older with impaired kidney function and have more multimorbidity and polypharmacy. We propose a novel two-stage screening approach to detect and evaluate clinically relevant drug-drug interactions that could affect the safety profile of newer diabetes medications in patients with DKD (Aim 3). This proposal will advance our understanding of these drugs’ safety and, thus, will help overcome barriers to prescribing in patients with DKD who may largely benefit from them. The filling of critical knowledge gaps and new insights regarding safe prescribing will significantly influence the clinical management of patients with DKD.

NIH Research Projects · FY 2026 · 2024-04

Project Summary/Abstract Coronary heart disease (CHD) remains among the leading causes of deaths in the U.S. While a sedentary lifestyle, unhealthful diets, smoking behaviors, and genetic predispositions are established risk factors of CHD, emerging evidence suggests that environmental pollutants, such as per- and polyfluoroalkyl substances (PFAS), may also contribute to the CHD etiology. Potential connections between PFAS exposures and dyslipidemia have been extensively examined in epidemiological studies, although significant heterogeneity among studies was observed. More recent evidence suggests that PFAS may particularly interfere with the metabolism of pro-atherogenic lipoprotein subspecies that carry apolipoprotein CIII and other apolipoproteins, which are significantly associated with CHD risk in multiple prospective studies. This new evidence points to a new pathway through which PFAS may influence CHD risk. Data are still sparse regarding the inter- relationships among PFAS, lipoprotein subspecies, and incident CHD risk in the U.S. population who are ubiquitously exposed to PFAS. The proposed research aims to address these important knowledge gaps by conducting cross-sectional and longitudinal investigations to substantiate the associations of PFAS with lipoprotein subspecies and CHD risk in four well-characterized U.S. cohort studies consisting of ethnically- diverse participants: the Health Professionals Follow-up Study, Nurses’ Health Study (NHS), NHSII, and Hispanic Community Health Study / Study of Latinos (SOL). The rich, existing resources and data allow the investigators to cost-effectively examine these study aims: 1) to examine various PFAS in relation to lipoprotein subspecies in blood samples repeatedly collected during the past three decades; 2) to evaluate longitudinally the changes of PFAS in relation to the contemporaneous changes of lipoprotein subspecies in repeat blood samples collected ~10 years apart in the NHS/NHSII and SOL cohorts; and 3) to investigate prospective associations between PFAS and CHD risk and to explore the role of the lipoprotein subspecies in these associations of interest. Besides filling the knowledge gaps, the innovation of the proposed research also lies in the coverage of some newly emerged PFAS that can only be meaningfully measured in blood samples collected recently, the examination of longitudinal relationships between PFAS and lipoprotein subspecies, and the inclusion of Hispanic participants from the SOL cohort. A highly experienced investigator team consisting of environmental and cardiovascular disease epidemiologists, lipoprotein and PFAS research experts, and biostatisticians has been assembled to achieve the study goals in a timely fashion with great qualities. Data from this proposed research will shed light on the role of PFAS exposures in modulating lipoprotein subspecies and CHD risk in U.S. populations. Such evidence may also aid in policy-making processes for making more evidence-based regulations toward the production and use of PFAS in the U.S.