Brigham And Women'S Hospital

NIH Research Projects · FY 2025 · 2025-09

A large proportion of people with Down syndrome (DS) will exhibit Alzheimer's Disease (AD) neuropathology and will eventually develop dementia by age 60. The prevention and treatment of dementia is a high priority for people with DS and their families. Thus, there is an unmet need for strategies that can prevent, treat, or slow the progression of AD in people with DS. NAD+ depletion and dysregulation of NAD-dependent pathways are associated with increased tau phosphorylation and amyloid β accumulation, neuro-inflammation, dysregulated mitochondrial bioenergetics and neuro-degenerative changes in the brain similar to those observed in AD. In contrast to many AD drugs that target one mechanism, the NAD+ precursor, nicotinamide mononucleotide (NMN), targets AD neuropathology by multiple mechanisms: reducing the synthesis of oligomerized Aβ peptides and Aβ toxicity; increasing α-secretase activity; attenuating neuroinflammation; promoting neuronal regeneration; and improving mitochondrial energetics. Administration of oral NMN safely raises NAD+ levels in the blood and some other tissues in healthy adults. Thus, NMN is a promising candidate drug to prevent and treat AD but its safety, pharmacokinetics (PK), and pharmacodynamics (PD) have not been evaluated in people with DS. In accord with the reviewers' recommendation, we propose this multiple ascending dose, placebo-controlled, phase1 trial to determine the safety and tolerability, as well as PK and PD of NMN in adults with DS, as a first step towards evaluating its efficacy. The safety and tolerability will be assessed by structured monitoring of adverse events, safety laboratory tests, and electrocardiograms. The PK of oral, multiple ascending doses of NMN will be assessed starting with the 500 mg daily dose and escalating the dose in ascending order to the maximum dose of 1000 mg twice daily or a maximal tolerated dose. PK parameters (Caverage 0-24 h, Cmax, Tmax, z, AUClast, AUC24hr, AUCinf, and T1/2) will be computed using nonparametric methods. The PD will be assessed by analyzing blood NAD+ concentrations and circulating NAD+ metabolites (nicotinamide, 1- methylnicotinamide, N-Methyl-2-pyridone-5-carboxamide, N-Methyl-4-pyridone-3-carboxamide, nicotinic acid, and nicotinuric acid). We will determine whether oral NMN increases brain NAD+ levels, measured by ultra- high field 7T magnetic resonance spectroscopy (MRS). Exploratory outcomes include blood pressure and lipids that were improved in earlier human studies with NMN, muscle performance, and physical function. The trial is not long enough or large enough to evaluate effects on AD biomarkers or neuropsychological outcomes. The selection of a candidate drug that targets multiple AD mechanisms, innovative methods, rigorous trial design, and an inter-disciplinary team with substantial expertise in all content areas will facilitate accomplishment of the stated aims. The trial will provide important information on the safety, PK, and PD that is necessary for guiding the stepwise progression of this promising molecule towards larger efficacy trials.

NIH Research Projects · FY 2025 · 2025-09

Since people living with dementia (PLWD) are vulnerable to medication errors, drug-drug interactions, and a variety of adverse drug events, their prescribing decisions need to be informed by solid evidence. Physicians’ prescribing decisions often rely on routinely collected data because randomized controlled trials (RCTs) often severely underrepresent people living with dementia (PLWD). Electronic health records (EHR) are among the most commonly used real-world data for comparative effectiveness research (CER) because they contain rich clinical data. However, the structured EHR data suffers from missing data on key geriatric factors critical for conducting valid comparative effectiveness research (CER) among PLWD, such as degree of cognitive impairment, mental and functional status, and behavioral symptoms. Much of such information is embedded in the free-text clinical notes and reports, but traditional natural language processing (NLP) requires a labor- intensive data annotation process for each target phenotype, which is not scalable for the large numbers of study variables needed for confounding adjustment in a non-randomized CER study. Large Language Models (LLMs) have been shown to have promising potential to extract concepts and phenotypes that were not predefined during a training stage. However, the performance of the existing LLMs in predicting ADRD-relevant phenotypes is unknown. None of the existing LLMs have been trained on clinical EHR notes linking to external data that contain longitudinal geriatric data. Our objective is to build novel LLMs specializing in ADRD-relevant CER. It is designed to generate ADRD-relevant phenotypes and trained on clinical EHR integrated with multiple geriatric- information-enriched external datasets. The ground truth of all phenotypes our LLMs aim to predict will be provided by large-scale annotation available as structured data in the linked external datasets. Our integrated dataset will cover >850,000 lives (>80,000 PLWD) in two large multi-center EHR networks in Massachusetts from 2000-2024. The central hypothesis is that LLMs can be used to scalably generate valid features and consistently reduce missing data on key geriatric factors, enhancing the robustness of causal CER analyses among PLWD. Building on existing general-purpose LLMs, we will develop novel LLMs by instruction-tuning, converting the linked structured labels into text instructions and finetuning the LLMs through a text generation framework, and by chain-of-thought technique, guiding LLMs to infer results via multiple reasoning steps. In Aim 1, we will continual pre-train and finetune novel LLMs to determine eight categories of geriatric-specific phenotypes commonly used in ARDR-relevant CER. In Aim 2, we will assess generalizability by testing the performance to determine eight additional phenotypes not previously targeted and optimize the LLMs accordingly. In Aim 3, we will compare the treatment effect estimation using only EHR (mimicking the common research scenario when linkage to external data is infeasible due to privacy concerns) with vs. without using the LLM- derived features in six highly relevant empirical drug safety and effectiveness studies among PLWD.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Allogeneic hematopoietic stem cell transplant (HCT) recipients are at high risk of severe morbidity and mortality due to respiratory viral illnesses, including COVID-19. Despite two mRNA SARS-CoV-2 vaccines that are highly effective for the general population, HCT recipients have reduced immune responses to vaccines and remain at risk. This population’s ongoing risk is amplified by the emergence and circulation of SARS-CoV- 2 variant strains, relaxation of mask mandates and other public health measures, and waning effectiveness of SARS-CoV-2 monoclonal antibodies. New vaccination strategies are urgently needed for patients with hematologic malignancies, both to protect these patients and to reduce viral reservoirs that otherwise would allow for generation of new variants. To inform these strategies, we will evaluate the unique role of adoptive transfer of humoral and cellular immunity in HCT recipients, which will simultaneously use vaccine response as a mechanism to evaluate immune reconstitution. These studies will test our overarching hypothesis that these patients have distinct and altered immune responses to mRNA SARS-CoV-2 vaccination, resulting from their underlying disease, past immunomodulatory therapies, and the unique donor-to-recipient immune dynamics. The Specific Aims of this proposal are: Aim 1: Characterize the relationship between donor and recipient SARS-CoV-2 immunity in matched-related donor allogeneic HCT patients through analysis of humoral responses and transfer of immunity post-transplant from banked samples; Aim 2: Describe the correlation between donors’ pre-harvest cellular responses and recipients’ post-transplant humoral SARS-CoV-2 vaccine responses through creation of a prospective study of HCT recipients and their matched-related donors; and Aim 3: Evaluate donor v. recipient Ag-specific T and B cells and SARS-CoV-2 clonal breadth and depth after re-vaccination post-transplant to assess immune reconstitution, using T and B cell receptor repertoire analyses methods. We expect that completion of these aims and the associated training objectives will generate clinically applicable preliminary data to inform vaccine development and policy for patients with hematologic malignancies. My long-term career goal is to become an independently funded clinician-scientist and leader in translational vaccinology with a focus on developing precision vaccines for immunocompromised adults. I will achieve this through: 1) investigation of immunologic pathways that promote or inhibit vaccine-induced responses for patients with hematological malignancies, and 2) translation of these findings into novel vaccines via early-phase clinical trials. Brigham and Women’s Hospital and the Precision Vaccines Program at Boston Children’s Hospital are highly collaborative research environments within the broader Harvard Medical School community that will provide abundant resources and institutional support to complete the described aims.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT In pulmonary arterial hypertension (PAH) inflammation and endothelial dysfunction promote fibroproliferative pulmonary arterial remodeling, right ventricular failure (RV), and early death despite modern PAH therapies. Patients with mild pulmonary hypertension (PH) have increased risk for functional impairment, disease progression, and death, which emphasizes an unmet clinical need to identify strategies to target pulmonary vascular remodeling at an earlier clinical stage, especially for patients such as those with inflammatory connective tissue diseases (CTD), who are at higher risk for poor outcome compared to other PAH populations. However, the molecular mechanisms regulating fibroproliferative pulmonary vasculopathy in early PAH are not known, as preclinical investigation relies on the use of end-stage lung tissue and cells. Using network medicine analysis, we identify C-terminal src kinase (Csk), a CTD-associated inhibition of the oncoprotein Src, as a mediator of endothelial cell dysfunction and fibrosis in an inflammatory model of early PAH. To study Csk in relation to endothelial dysfunction, we developed a model of endothelial inflammation which induces collagen accumulation, pro-fibrotic Src activation, and endotypes observed in PAH human pulmonary artery endothelial cells (HPAECs). Inflammation also upregulated collagen 22 (Col22A1), a fibril-associated collagen linked to CTD risk and malignancy, which we show is upregulated in human PAH and in early inflammatory PAH in vivo, an event that is Src-dependent in vitro. We observed that inflammation induced these phenotypes despite an overall upregulation of Csk expression, which raised the possibility that Csk may become dysfunctional through a deleterious post-translational modification. Indeed, in HPAECs, we identify failure of Csk to inhibit Src in the setting of inflammation. The central goal of this proposal is to identify the molecular mechanism regulating Csk dysfunction and the functional consequences of this mechanism for pulmonary vascular Col22A1 in early PAH. We propose the following specific aims: 1) Test the hypothesis that inflammation promotes Csk dysfunction and Src activation in HPAECs and 2) Define the pulmonary vascular phenotype of Csk-dependent Col22A1. Understanding Csk-Src dependent Col22A1 vasculopathy may identify strategies to target the inception of pulmonary vascular remodeling, which may have implications for PAH prevention in high risk CTD patients.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Ubiquitination is a post-translational modification responsible for maintaining protein homeostasis within the cell. The HECT E3 ligases are a family of enzymes that catalyze ubiquitination, and dysregulation of this family of proteins is responsible for the pathogenesis of many diseases. In particular, the E3 ligase NEDD4 has been implicated in neurodegenerative disease, cardiovascular disease, and cancer. Despite the implication of NEDD4 in many diseases, studies of this E3 ligase have been hindered by a limited understanding of the structural dynamics of the HECT domain, which catalyzes ubiquitination, and the lack of selective small molecule probes. This proposal aims to elucidate the conformational dynamics of the NEDD4 HECT domain and use this information to develop small molecule inhibitors of NEDD4. Aim 1 will investigate the structural dynamics of the HECT domain. An NMR spectrum of the NEDD4 HECT domain will be obtained and assigned using different labeling techniques and NMR pulse sequences. Next, this assigned spectrum will be used to study the conformational changes of the HECT domain in different steps of the ubiquitination process by incubating the HECT domain with different protein partners and obtaining corresponding spectra. Finally, the kinetics of these conformational changes and the preference for each conformational state will be determined using a series of relaxation, saturation, and exchange NMR experiments. Aim 2 will afford small molecule inhibitors of NEDD4 and evaluate their efficacy in various cancer cell lines. Structure–activity relationship studies will be performed on a molecule previously identified in an in silico screen and analogues will be evaluated in a plate-based high throughput assay. This inhibitor will then be validated and characterized to determine its binding site and mechanism of inhibition. Finally, this inhibitor will be tested in various cancer cell lines in which NEDD4 has been identified to contribute to the promotion of cell proliferative activity. This proposal will deepen the understanding of the conformational changes the NEDD4 HECT domain undergoes to ubiquitinate its substrates and afford a small molecule inhibitor that can be used as a probe to understand the potential of NEDD4 as a therapeutic target. This proposal will be performed at Brigham and Women’s Hospital, Harvard Medical School, and Dana-Farber Cancer Institute all of which have the resources necessary to support this research. These institutions provide a collaborative, interdisciplinary environment critical to the success of this project. This proposal will also equip the applicant with new skills in protein engineering, enzymology, and protein NMR, preparing him for an independent academic career in the field of chemical biology. In addition to acquiring new technical skills, the applicant will develop his oral and written communication skills through manuscript preparation, grant writing, and presentations of his findings in departmental seminars and national conferences. He will also continue to teach and mentor undergraduate and graduate students affording him the necessary mentorship skills needed in academia.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Over 6 million individuals die from traumatic injuries annually, with 40 million permanently injured. Trauma care innovations developed in resource-constrained settings often provide breakthrough solutions that enhance emergency medical systems globally, including in the United States. Guatemala has a high injury burden with no structured prehospital system. Care falls to "bomberos"—mostly volunteer firefighters without medical training or health system integration. Geographic challenges and traffic extend transport times while patients receive no care en route, arriving at overwhelmed hospitals unprepared for their management. This causes critical delays in definitive treatment for patients who could benefit from established interventions like tourniquets. Research shows that accurate prehospital triage with advance hospital notification significantly improves trauma outcomes. Our team previously collaborated with bomberos in Guatemala to create a mobile and physical-simulation platform for training on essential prehospital hemorrhage control techniques and successfully trained bomberos to apply tourniquets with high proficiency. To address critical prehospital needs worldwide, we propose Rapid Emergency Skills for Prehospital Optimization, Notification, and Delivery (RESPOND) mHealth, a comprehensive, gamified, AI-powered program that delivers three integrated solutions to bomberos: (1) context-adapted basic emergency prehospital skills training; (2) a reliable mechanism for accurate triage and prompt hospital notification; and (3) a bombero community-of-practice with AI-powered decision support and consensus guidelines to aid management decisions, triage classifications, and sustainable learning. We will focus on well established components of emergency prehospital care (e.g. basic airway management, spinal immobilization, hemorrhage control, accurate triage and transportation). The innovative AI-powered training, consensus-generation, and decision-support platform developed through this research will inform improvements to US emergency medical services, particularly benefiting rural American communities. We hypothesize that the RESPOND program will improve the proportion of patients who arrive at the hospital with appropriate prehospital interventions and with accurate prehospital notification for the sickest patients. In the R21 phase, we will Aim 1: Develop the RESPOND mHealth application software and context- adapted content; Aim 2: Assess RESPOND mHealth training efficacy, validity, and app usability in a sample of 35 bomberos; Aim 3: Establish considerations for implementation through stakeholder interviews at Roosevelt Hospital in Guatemala City. In the R33 phase, we will: Aim 1: Implement RESPOND with two bombero companies servicing Roosevelt Hospital; Aim 2: Measure RESPOND impact on trauma triage, patients, bomberos, and hospital stakeholders using a prospective cohort design and qualitative methods; and Aim 3: Assess sustainability and scalability of the RESPOND program. If successful, this work will enable accurate recognition of life threatening injuries, effective delivery of basic prehospital care, and efficient interface with the hospital in a challenging, resource-constrained environment while generating innovations that benefit prehospital systems worldwide.

NIH Research Projects · FY 2025 · 2025-09

PROJECT ABSTRACT Newborn screening (NBS) by whole genome sequencing (NBSxWGS) offers the potential to identify infants at risk for genetic conditions that are treatable or preventable early in life. Integrating NBSxWGS into the existing U.S. state- and territorial-based Public Health Laboratory (PHL) systems as a first-tier screening method presents substantial practical and ethical challenges. Our NBSxWGS Collaboratory team (the “Collaboratory”) combines the experience of complementary teams that are leaders in the fields of newborn genomic screening and PHL implementation to assess the real-world feasibility of such integration. The ScreenPlus team has conducted NBS research utilizing multilingual in-person recruitment, collection of routine dried blood spots for research, and seamless integration with the New York State PHL to successfully recruit, screen and deliver results to over 65,000 infants at six hospitals for a lysosomal disorders supplemental pilot and over 28,000 additional infants at eight hospitals for an analyte plus gene sequencing approach. The BabySeq team has coordinated multi-site enrollment, randomization, and data collection from over 1,000 infants in the first year of life at nine U.S. recruitment sites to gather medical, behavioral and economic outcomes of newborn sequencing using whole exome/genome sequencing. The Association of Public Health Laboratories (APHL) is the sole national organization dedicated to the interests of PHLs, and operates a centralized secure, web-based data repository with harmonized performance metrics from nearly all U.S. NBS programs. APHL has executed 51 Data Use Agreements representing more than 99% of U.S. newborns, 70 implementation funding awards for expanded NBS, 16 site reviews, and over 20 molecular program assessments using a community-informed framework. GeneDx has evaluated over 750,000 clinical exomes and genomes, has clinically classified over one million variants, and has experience in NBSxWGS using residual blood spots from over 18,000 infants in New York State and North Carolina. We secured in-kind support from Illumina and GeneDx to provide high quality CAP/CLIA-accredited WGS, variant interpretation, and orthogonal confirmation for a to-be-selected gene panel in up to 30,000 infants at no cost to the Collaboratory, allowing the full NIH budget to support other critical feasibility activities. Ariadne Labs has expertise in implementation science, which it will contribute to this program. In partnership with a Community Advisory Board (CAB) our multidisciplinary, multi-state team of leaders in the ELSI of NBS will be embedded in the study and will guide, monitor, and study the ELSI of all aspects of the study. Our assessment of feasibility focuses on scientific feasibility, encompassing gene selection, WGS pipeline performance, variant interpretation, confirmatory testing, and medical follow-up; programmatic feasibility, reflecting the ability to implement efficient, scalable workflows across birthing centers and PHLs in multiple states; and human feasibility, addressing parental consent, uptake, acceptability, and communication among all stakeholders. These three dimensions correspond to widely used domains of feasibility in implementation research, enabling a comprehensive framework for evaluating NBSxWGS in public health. An early and essential goal will be to establish consensus among the Collaboratory academic team, APHL, CAB, PHLs, and NIH on criteria and thresholds that will define Scientific, Programmatic, and Human feasibility and to explore these through the four Functions outlined in the Research Opportunity Announcement. Our team brings unparalleled strengths to each Function of the Collaboratory. The goals of Function 1 are overall administration, onboarding of PHLs, establishing the Community of Practice, IRB approvals, and communication among all stakeholders - building upon our deep experience in coordinating interdisciplinary teams and large genomic trials in infants (ScreenPlus, BabySeq and APHL’s administrative credibility and leadership among the PHLs). The goals of Function 2 are to establish the workflow for recruitment, consent and return of results, building upon the experience of both ScreenPlus, BabySeq, and prior studies in recruiting, enrolling and returning genomic results. The goals of Function 3 are to sequence, confirm, and report on a study-created, agreed-upon gene list - building upon our experience developing a gene list through consensus and the expertise of GeneDx as a leading U.S. sequencing center. The goals of Function 4 are to create and fully embed CAB and ELSI perspectives, and with the entire Collaboratory, explore the tensions surrounding consent, parental understanding of risks, benefits, privacy and distress - led by national ELSI experts in NBS, and building on their ELSI work. Our team brings additional innovation by (1) integrating exclusively with the existing APHL infrastructure, and (2) conducting two embedded studies comparing in-person postnatal vs. hybrid prenatal recruitment (within Function 2) and a longitudinal cohort study to examine the psychosocial impact of positive WGS results (within Function 4). Together our Collaboratory of national leaders across the full spectrum of NBSxWGS brings the vision, expertise, and infrastructure necessary to rigorously evaluate the scientific, programmatic, and human feasibility of implementing NBSxWGS at scale in a way that is both sustainable for public health systems and trusted by families nationwide.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT High levels of lipids, such as cholesterol, are a major risk factor of development of atherosclerotic cardiovascular disease (ASCVD), which promote plaque formation inside arteries. Despite the success of current lipid-lowering therapies (e.g., statins and PCSK9 inhibitors), ASCVD remains one leading cause of mortality. This may be due to the lack of effective and safe strategies that can concurrently reduce cholesterol synthesis in the liver and curb arterial inflammation in the atherosclerotic lesion. The long-term objective of this project is to develop a new lipid- lowering and anti-inflammatory siRNA therapy for more effective treatment of ASCVD, based on i) the discovery of new biological roles of Epsin endocytic adaptor proteins in hyperlipidemia and atherosclerosis by Dr. Chen (MPI) and ii) the development of long-acting, dual tissues-targeting siRNA lipid nanoparticles (LNPs) by Dr. Shi (MPI). We recently revealed that Epsins regulate lipid metabolism and transport in atherosclerotic macrophages, and that silencing macrophage Epsins leads to reduction of arterial inflammation and atherosclerotic plaque size. In new preliminary studies, we also discovered that Epsins in liver hepatocytes contribute to hyperlipidemia by promoting cholesterol synthesis and reducing low-density lipoprotein cholesterol (LDL-C) clearance. Thus, we expect that co-targeting of Epsins in both the liver and atherosclerotic lesion will effectively restrict hyperlipidemia and arterial inflammation in atherosclerosis. In parallel, we have lately developed a novel LNP platform that can dramatically prolong the duration of efficient siRNA silencing after a single intravenous injection, as compared to traditional siRNA LNPs. By further engineering our new siRNA LNPs, we can simultaneously silence Epsins in the atherosclerotic plaque and liver. In light of these promising data, we hypothesize that our long-acting siRNA LNP platform for dual tissues-targeting of Epsins could lead to development of a new, more potent lipid-lowering and anti-inflammatory therapy for ASCVD. Here, we aim to i) further optimize and understand the long-acting siRNA LNPs; ii) tune the siRNA LNP surface chemistry for sufficient co-targeting of the liver hepatocytes and lesional macrophages in vivo; and iii) systematically evaluate the efficacy and safety of our siEpsins LNPs in various mouse and rabbit models of atherosclerosis. The successful completion of this MPI project could facilitate the development of next-generation therapeutics for ASCVD.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Abstract Alzheimer disease (AD) is the most common form of dementia that has no cure and few therapeutic options, and the strongest risk factor for developing AD dementia is aging, an unavoidable event. T cells are greatly affected during aging as they become comprised of less naïve/resting cells and more terminal differentiated/senescent cells that can be cytotoxic and produce high amounts of pro-inflammatory cytokines. Inflammation is known to be an early event in AD with innate microglial activation and an augmented cytokine production in the CNS and increases in frequency of circulating Th1, TH17 and Th9 inflammatory T-cells. Functioning in distinct contrast to these inflammatory T cells, are regulatory T cells (Tregs) which are a small, usually stable, lineage of inhibitory CD4 T cells that expresses the FoxP3 transcription factor and is essential for maintaining healthy homeostasis and tolerance. Tregs appear to be involved in AD pathology as most reports have found them to be at low frequency in the AD patient circulation, while mouse AD models demonstrate that Tregs can affect the disease as the adoptive transfer of Tregs slows disease progression. The ability of Tregs to down modulate inflammation makes them central to immune resolution and inhibition of autoimmunity. But Tregs have additional far-reaching activities as they not only can inhibit the activation of microglia and other immune lineages (B, T, monocyte), but also can initiate tissue repair and recovery. Tregs have been shown to be neuroprotective in mouse models for brain hemorrhage and for the neurodegenerative diseases Parkinson’s, ALS, and AD. Excitingly, the administration of wild type Tregs into the APPPS1 AD mouse model was found to slow disease and also induce recovery of cognition. Yet, only one group has actually isolated and performed the in vitro functional assays needed to determine if AD patient-derived Tregs are functionally competent or if their reduced activity would represent a potential therapeutic target. Unfortunately, this study used suboptimal Treg isolation methods, combined functionally-distinct Treg subsets into a single population, and analyzed only one parameter to assess Treg function – suppression of target cell proliferation. Thus, it is crucial that a more comprehensive study be performed to reveal the breadth of potential dysfunction of Tregs in AD-dementia and expose dysfunction-inducing mechanisms. As our lab routinely examines human Treg function in disease, we have begun to study AD-Tregs using a high stringency isolation and multi-parameter functional assay approach that separately interrogates functionally distinct subsets of Tregs isolated from pairs of matched AD-dementia vs HC PBMCs. Our overarching goal is to uncover if and why Tregs show dysfunction in AD. Illuminating the mechanisms of Treg deficiency in AD will contribute to future development of Treg-directed therapies for AD, where optimal Tregs may slow progression, induce tissue repair and restore cognition.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT HIV is the most important risk factor for progression to active tuberculosis (TB), but the immunologic mechanisms for this increased rate of progression are incompletely defined. Antibodies serve an important role coordinating the innate and adaptive immune compartments through the Fc-domain of the immunoglobulin molecule. Antibody production and Fc features are known to be broadly dysregulated in HIV infected individuals. This proposal will test the hypothesis that perturbations to antibody Fc-mediated functions contribute to increased risk in HIV infected individuals. This proposal presents a five-year research career development program to comprehensively investigate the roles of antibody-dependent effector functions in TB progression in the setting of HIV coinfection. Prior data indicate antibodies can predict TB progression in HIV-negative individuals and can confer protection against Mtb infection in vitro. Preliminary data presented here indicates that Ab functional features, and specifically neutrophil-activating functions, are altered in HIV co-infection. Published data suggest that neutrophils can play both pathogenic roles in TB (such as NETosis) and putatively protective roles (such as phagocytosis). In the studies proposed here, we aim to 1) apply expanded effector functional profiling to evaluate the impact of HIV on the breadth of Fc-mediated effector functions, and 2) define the antibody-dependent functional correlates that predict TB progression and Mtb antimicrobial control in the setting of HIV co-infection. We will leverage human plasma samples from two unique international cohorts: for Aim 1, we will use a Ugandan cohort of individuals with latent TB infection to investigate the impact of HIV on Mtb-specific antibody functionality; for Aim 2, we will use a multinational longitudinal cohort of HIV-coinfected TB progressors to evaluate both cross-sectional and temporal differences in Fc-mediated effector function. We will use innovative experimental and analytic methodologies including a high-throughput systems serology platform, in vitro functional assays measuring the ability of antibodies to drive NK cell activation, monocyte phagocytosis, complement deposition, and an expanded suite of neutrophil functions, and validated in vitro antimicrobial growth restriction assays. The candidate is currently an Instructor in Medicine at Brigham and Women’s Hospital with an ongoing research commitment of 75% time. The proposal is supported by an expert mentor in TB immunology and mycobacteriology, Dr. Sarah Fortune at the Harvard School of Public Health. The training plan unites the candidate’s postdoctoral training in humoral immunology with specific training in innate immunity, TB immunology, TB pathobiology, and bioinformatics, as well as ongoing professional development coursework. Completion of this comprehensive training plan will ensure the candidate’s successful development of a unique independent translational research program focused on Fc effector functions and systems immunology.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT The overarching goal of this project is to comprehensively quantify changes in metabolites and pathways (collectively, the metabolomic profile) associated with oral contraception (OC) use to elucidate mechanisms involved in ovarian and breast carcinogenesis. Ovarian cancer (OvCa) is the 5th most common cause of cancer death among females, but risk is 15-30% lower among women who have ever used OCs. Conversely, epidemiologic studies also show modest but significant increased risk of breast cancer (BrCa), the most common cancer of US women, with OC use. One approach for disentangling the effects of OCs on cancer risk and elucidating etiology is the integration of metabolomics into epidemiologic research. Recent studies support circulating plasma metabolites and metabolite groups are associated with OvCa and BrCa, and that OCs can change metabolomic profiles. However, key barriers to determining the mechanisms of OC use that contribute to cancer risk include: 1) limited details of OC use in large cohorts (e.g. formulation, duration, age at first use), 2) inadequate consideration of individual variability in physiologic response to OC use (e.g. metabolizing enzyme activity, endometriosis (OvCa risk factor), family history of OvCa/BrCa), and 3) lack of biospecimens representing the local environment relative to the cancer site of origin (e.g. peritoneal cavity for OvCa). Dr. Mongiovi will address these limitations in an assessment of metabolites associated with OC use using a machine learning and systems biology approach. Leveraging data from the Nurses’ Health Studies (NHS, NHSII) and the Women’s Health Study: From Adolescence to Adulthood (A2A), Aim 1 (K99) will identify circulating metabolomic profiles of current OC use among premenopausal women and prior OC use among postmenopausal women and evaluate differences by genetic variants in hormone biosynthesis and metabolism pathways, endometriosis status, and family history. Metabolite profile scores of current and prior OC use will be developed and the association of each metabolite score with risk of OvCa and BrCa will be determined in nested case-control studies within NHS/NHSII. Aim 2 (R00) will characterize local metabolomic profiles relative to the development of BrCa in normal breast tissue from then Komen Tissue Bank, OvCa using previously collected peritoneal fluid from A2A participants, and novel assessment of vaginal fluid among women recruited from local clinics. The proposed research will elucidate how OCs alter OvCa and BrCa risk by comprehensively assessing systemic and local metabolomic profiles. By disentangling the processes through which OC leads to reduced OvCa and increased BrCa risk through metabolomic profiling, we can improve risk prediction and identify targets for prevention and interception. During the K99 phase, Dr. Mongiovi will follow a well-rounded training plan in support of these aims developing proficiency in analysis and interpretation of omics data and cultivating expertise in ovarian and breast tumorigenesis. This K99/R00 award will support her in obtaining the knowledge and experience to effectively pursue a career as an independent, interdisciplinary researcher in female cancers.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract This R03 award will contribute to providing Dr. Katherine Ravi with the resources, additional training and protected time necessary to achieve her goal of becoming an independent clinical investigator. Dr. Ravi has completed her Master of Public Health and will continue to benefit from her outstanding institutional support and resources through the pursuit of didactic courses for continued formal education in biostatistics and study design through Harvard Catalyst and the Harvard Master of Medical Sciences in Clinical Investigation program, research conferences, leadership courses and training in the responsible conduct of research. These will complement her strong institutional support and will build upon her prior training in human investigation. Well over a million patients have initiated hemodialysis in the last decade in the United States alone, and their mortality rate during their first year on hemodialysis is nearly 20%. The risk of death is particularly high in the first 120 days after starting hemodialysis, with cardiac arrest of unknown cause occurring at a rate of 5.2 per 100 person-years during this period. It has been demonstrated that the first week of hemodialysis is associated with the highest rate of cardiovascular events. However, few studies have assessed cardiac rhythms during the particularly vulnerable hemodialysis initiation period. This R03 proposal (PAR-22-129), entitled “Incident Hemodialysis Electrolyte Analysis and Rhythm Trends (IHEART)” will investigate how cardiac rhythm morphology associated with sudden cardiac death evolves during the early stages of hemodialysis, and how serum electrolyte levels are associated with these changes. We will perform a cohort study on 30 patients initiating hemodialysis; we will recruit 33 patients total to allow for a 10% dropout rate. In Aim 1, we will compare QTc duration, ventricular ectopy, heart rate variability (all markers of sudden cardiac death and arrhythmia risk) and arrhythmia in week 1 and week 5 of hemodialysis initiation. In Aim 2, we will assess how electrolytes are associated with these changes, with a focus on ionized calcium levels. During this award period, Dr. Ravi will employ her excellent academic resources and mentorship at Brigham and Women’s Hospital to continue in her pursuit of skills and expertise required to attain R01 funding, allowing her to continue her critically important research and to train future clinical investigators.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Systemic lupus erythematosus (SLE) is a heterogeneous disease characterized by IgG-antibody-antigen immune complexes (ICs). About 50% of patients develop lupus nephritis, up to 36% develop vasculitis that can lead to life-threatening cardiac inflammation, and the presence of lupus nephritis increases the incidence of cardiovascular events. Immune cell abnormalities underly these processes but the mechanisms driving them are poorly understood. Both activated neutrophils and self-reactive T cells activated by antigen presenting cells (APCs) play roles in disease pathogenesis. Conventional dendritic cells, cDC1s are recognized as the professional APCs for their unique ability to activate naïve T cells and cross-present extracellular antigens to CD8 T cells. We detected neutrophils with markers of APCs, termed nAPC, in patients with lupus nephritis and the frequency of nAPCs clinically correlated with disease activity. Accordingly, we show that the interaction of ICs with FcγRs on neutrophils generates highly immunogenic APCs (nAPCs). In FcγR humanized mice expressing the human FcγRIIIB only on neutrophils, an anti-FcγRIII mAb conjugated to a model T cell antigen, Ovalbumin (αRIII-Ova) (replicating the effects of FcγRIIIB’s natural ligands, i.e. small ICs), robustly expands naïve Ova-specific CD4 and CD8 T cells compared to IgG-Ova control, even in the genetic absence of cDC1s. In the context of nephrotoxic nephritis (NTN), a model of crescentic glomerulonephritis mimicking the effector phase of lupus nephritis, αRIII-Ova further expands Ova-specific T cells compared to IgG-Ova that migrate to the nephritic kidney and accumulate in the renal draining LNs (dLN). We will test the hypothesis that circulating ICs containing self-antigens in SLE generate nAPCs that initiate the activation of self-reactive T cells in 2o lymphoid organs and with the assistance of nAPC activated cDC1 induce T cell trafficking to tissues and dLN that fuels systemic autoimmunity and increases the risk for secondary coronary vasculitis. Our studies will use NTN, an inducible model of coronary vasculitis, scRNA-sequencing, multiplexed spatial imaging of the spleen from NTN mice and human lupus patients with and without nephritis, and CRISPR/Cas9 based neutrophil or T cell specific deletion of genes of interest. This proposal is innovative as it suggests that IC-stimulated neutrophils play a central role in initiating and perpetuating T cell mediated dysfunction in glomerulonephritis and subsequent secondary cardiac inflammation. It is significant as it may offer new insights into disease pathogenesis, addresses a substantial unmet clinical need, and provides knowledge that can be used to develop novel targeted therapeutic interventions that disrupt neutrophil-mediated T cell dysregulation in both glomerulonephritis and secondary coronary vasculitis in lupus. Importantly, the function of nAPCs can’t be assumed by more conventional APC as nAPCs are immunogenic in the absence of adjuvant and FcγRs play a major role in neutrophil’s acquiring potent APC function.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY This is the Paul B. Beeson Emerging Leaders Career Development Award in Aging submission for Lisa Simon, MD DMD, an internal medicine physician, general dentist, and early-stage investigator whose work focuses on the impact of oral health access on health outcomes for older adults. Through this Career Development Award, she will strengthen her skills in advanced analytic techniques and mixed methods analysis and develop clinical expertise in the medical and dental care of older adults. Although oral health is an important component of overall health for older adults, Medicare has not historically offered a dental benefit. Through a policy change beginning in 2023, traditional Medicare has begun covering dental services for Medicare beneficiaries with certain eligible diagnoses: those undergoing organ transplant, cardiac surgery/valvuloplasty, those with head and neck cancer, and those with cancer receiving chemotherapy, intravenous bisphosphonates, or chimeric antigen receptor T-cell therapy. This policy change represents a novel opportunity to evaluate the effect of dental access on both the dental and medical outcomes of Medicare beneficiaries through the following specific aims, leveraging both advanced methods that support causal inference and qualitative analysis: 1) to determine the change in rates of dental visits and complete tooth loss among Medicare beneficiaries with conditions meeting eligibility for the new dental benefit; 2) to evaluate treatment effect heterogeneity of dental coverage for eligible Medicare beneficiaries by racial and ethnic identity, geography, and availability of dental care; and 3) to identify the barriers and facilitators associated with Medicare enrollment among dentists. In tandem, with the support of an exceptional mentorship team, Dr. Simon will pursue the following career development goals to enrich her research and leadership abilities. These goals are: 1) to develop expertise in geriatric medicine at the interface of medicine and dentistry to better understand the health needs of older adults; 2) to acquire advanced skills in data science methods including causal inference and claims data analysis; and 3) to develop proficiency in qualitative research and its application to aging policy. Brigham and Women's Hospital and Harvard Medical School are the ideal environment for research excellence, with a strong background in Medicare policy evaluation and advocacy for older adults. Upon completion of this Career Development Award, Dr. Simon will be uniquely equipped to achieve independence as a researcher in aging.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY: With increasingly efficacious strategies to treat HIV, the paradigm continues to shift to conceptualize HIV as a chronic disease. This has resulted in people with HIV (PWH) aging and developing chronic disease. Among HIV comorbidities, chronic pain is common and undertreated. This is a significant problem because untreated, chronic pain results in worsening psychiatric disease, increasing exacerbations of pain, and substance use. Additionally, persistent chronic pain among PWH results in disengagement with HIV care and worsening adherence to antiretroviral therapy (ART). Despite the ubiquity of chronic pain in PWH, treatment consisting of pharmacotherapy or psychotherapy is suboptimal. Pharmacotherapy options for chronic pain are limited and fail to address common psychological underpinnings of chronic pain in PWH while psychotherapy may be difficult to adhere to or access, especially among resourced limited settings where many aging PWH may seek care. In response to these extant challenges in addressing chronic pain among PWH, we propose the use of music as a biobehavioral intervention that addresses both psychological and biological aspects of pain. Grounded in the biopsychosocial model of pain and the NCCIH Whole Person Health model, our music-based intervention leverages preliminary data where we demonstrated that individuals with pain will use music to address catastrophizing, anxiety and other behavioral inputs of pain, and that listening to self-selected music induces changes that increase pain threshold and tolerance. Among a pilot cohort of PWH with chronic pain, we also demonstrated that listening to brief, 15-minute sessions of music induces significant improvements in negative affect and that PWH identify music as an acceptable strategy to help address their experience of pain. Based on this preliminary data, this proposal seeks to first develop a treatment manual to standardize the programming and delivery of an app that draws from streaming music services personalized by individual selection to create custom playlists surrounding key triggers of pain. Next, we will conduct a pilot randomized controlled trial to test the feasibility and acceptability of our music-based intervention among PWH with chronic pain. As part of this work, we will assess the feasibility of completing key study measures that assess the potential psychologic and mechanistic pathways addressed by music. The ultimate impact will be to advance a manualized music intervention that addresses pain in PWH as a feasible intervention in preparation for a multisite NCCIH R01 clinical trial.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Immune checkpoint inhibitors (ICIs) have revolutionized advanced cancer care, with up to 44% of all cancer patients eligible for ICI therapy as of 2019, representing 230,000 patients annually in the US alone. However, ICIs are associated with morbid and potentially fatal toxicities, known as immune-related adverse events (irAEs). In this work, we propose to study the genetic landscape of cutaneous irAEs (cirAEs) by analyzing germline data from thousands of ICI recipients and integrating with carefully collected spatial and longitudinal molecular data across multiple scales. No germline association studies of cirAEs have been performed to date, with an urgent need for discovery and functional follow-up. First, we will identify germline variants associated with cirAEs across >10,000 immunotherapy patients. We will investigate the genetic mechanisms of common germline variants; common and rare HLA alleles; as well as germline interactions with tumor and/or environmental features. Second, we will characterize the causal genes and phenotypic consequence of cirAE-associated variants. We will integrate population-scale RNA-seq data to identify the causal genes mediating cirAE events; we will investigate the downstream effects on anti-tumor response and overall survival; and we will identify associations with extremely severe cirAEs. Third, we will carry out prospective molecular phenotyping to map the precise mechanisms of cirAE risk in time and space for genotyped patients with skin cancer. For patients on ICIs, we will prospectively collect tissue for spatial profiling, TCR sequencing, and proteomics to comprehensively assay the precursors and consequences of cirAEs. If successful, our proposal will increase our understanding of the genetic architecture of cirAEs, identify avenues for therapeutic intervention and patient stratification to mitigate irAEs across organ systems, and potentially identify new ways of heightening the broader anti-tumor effect of ICIs.

NIH Research Projects · FY 2025 · 2025-09

The applicant seeks this K99/R00 award to achieve research independence focused on the integration of precision biomaterials and antiretroviral (ARV) therapy to innovate the treatment of HIV/AIDS. To achieve this goal, the applicant will receive training in three critical areas: (1) design of long-acting injectables (LAIs) to achieve sustained delivery of a broad spectrum of ARVs, (2) preclinical evaluation of LAIs in humanized HIV mouse models, and (3) pharmacokinetic analysis and modeling. She will receive guidance and comprehensive training through a detailed training plan from a mentoring team of experts (Drs. Joshi, Barouch, and Karp) with an established track record of mentoring junior scientists to independence. Her research will identify biodegradable LAIs that can provide sustained delivery of both hydrophobic and hydrophilic ARVs for at least 6 months with minimal initial burst and rapidly achievable steady- state plasma levels. During the K99 phase, she will investigate how the physicochemical properties of her LAI and ARV hydrophilicity can play a role in encapsulated ARV release and establish sustained prophylactic efficacy against HIV in a humanized mouse model. She will also tailor the LAI formulations to deliver a broad spectrum of ARVs, enabling single injection combination ARV therapy (cART) in vitro. This research goal, combined with the training and mentorship she will receive, will prepare her for independence in the R00 phase. During the R00 phase, she will utilize findings from the K99 phases for preclinical validation of sustained cART efficacy using her LAI in humanized mice and PK analysis in non-human primates. Ultimately, this research aims to provide a strong scientific rationale for future clinical trials, paving the way for a more accessible and effective approach to global HIV prevention and treatment that promotes health equity. Her findings during the K99 and R00 phases of this proposal will have a paradigm-shifting impact by providing robust scientific justification for future clinical trials, paving the way for a more accessible and effective approach to global HIV prevention and treatment, and promoting health equity. The K99/R00 award will thus provide the applicant with a platform for an independent career using versatile ultra-long-acting drug delivery, the HIV animal model, and human PK modeling to mitigate the HIV/AIDS epidemic.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY This K23 award will support career development for the candidate to become an independent acupuncturist- scientist, focused on mechanisms of acupuncture and point specificity. BACKGROUND. Acupoints represent one of the core tenets of acupuncture, yet their underlying scientific basis remains poorly understood. This gap poses challenges in advancing the fundamental science of acupuncture and determining whether point specificity is an essential, therapeutic component of acupuncture. Recent basic animal studies have provided compelling evidence that cutaneous neurogenic inflammation may be a potential physiological correlate of acupoints in the context of visceral diseases. They demonstrated that (1) experimental induction of visceral diseases (e.g., rodent models of colitis) causes cutaneous neurogenic inflammation, the distribution of which overlaps with the locations of specific acupoints, and (2) acupuncture at these sensitized locations is more effective in improving the corresponding diseases. To date, no studies have been done to validate these findings in human subjects. Thus, the goal of this K23 is to bridge this gap by conducting clinical and translational (C/T) research in human subjects, using inflammatory bowel disease (IBD) as the disease model. Key features of neurogenic inflammation include increased blood flow and hypersensitivity, so cutaneous blood perfusion and pressure pain threshold (PPT) will be collected as proxy measures, using laser speckle contrast imaging and pressure algometry. SPECIFIC AIMS. The proposal will consist of two independent, yet interrelated studies: a translational study comparing cutaneous blood perfusion and PPT between IBD patients and healthy control participants across multiple prespecified acupoints and sham points (Aim 1), and a pilot RCT in IBD patients to collect feasibility measures that will inform the design of a larger scale RCT, evaluating whether cutaneous sensitization of acupoints and/or sham points used in acupuncture treatment affects clinical outcomes (Aim 2). LONG-TERM GOAL. The candidate’s long-term career goal as an acupuncturist-scientist is to advance the science of acupuncture and translate scientific evidence to inform clinical practice to ultimately improve patient care. With the mentored research and training activities proposed in this K23, she will develop expertise in C/T research methodologies, learn more about IBD pathophysiology, deepen her understanding of biomedical imaging and biomarker science, and gain competence in longitudinal analysis. MENTORSHIP. The candidate will be supported an interdisciplinary mentoring team with expertise in acupuncture research, IBD, biomedical imaging and physiological signal analyses, and biostatistics: Drs. Peter Wayne and Vitaly Napadow (co-primary mentors) and Drs. Joshua Korzenik, Ted Kaptchuk, Weidong Lu, Andrew Ahn, and Pamela Rist (collaborators and secondary mentors). IMPACT. This K23 proposal addresses a critical gap in the field of acupuncture research surrounding the scientific basis of acupoints and aligns with NCCIH’s objective to advance the fundamental science and methods development relevant to acupuncture research.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT: Obesity, coronary artery disease (CAD) and heart failure represent 3 of the most important threats to US public health, yet there is limited understanding of how these chronic multimorbid conditions manifest differently across heterogeneous populations, including women versus men. Ischemia with nonobstructive coronary arteries (INOCA) captures a chronic condition that has newly emerged as a major contributor to adverse cardiovascular disease (CVD) outcomes, especially in women. Current evidence suggests that a large proportion of these women have coronary microvascular dysfunction (CMD). CMD is associated with increased risk of adverse CVD outcomes, including death, myocardial infarction (MI), and heart failure with preserved ejection fraction (HFpEF), especially in patients with obesity and cardiometabolic risk factors. Yet conventional diagnostic and therapeutic strategies, tailored for identification and management of male-pattern obesity and CVD, miss a majority of these at-risk women with INOCA, who represent an understudied population with high unmet clinical need. To optimally address the heterogeneity of obesity in these patients, we propose to apply cutting-edge diagnostic technology to investigate the role of body composition, CMD and HFpEF in characterizing adverse cardiometabolic phenotypes in INOCA. The overall goal of this proposal is to leverage novel, sensitive multimodality imaging tools to identify mechanisms of cardiometabolic risk in INOCA and clarify targets for future intervention in this patient population. The PI is an Early Stage Investigator (ESI) cardiologist and expert in CMD ideally positioned, together with Co-I experts in cardiothoracic radiology, artificial intelligence methods for body composition, and clinical weight loss interventions, to build upon strong preliminary data and existing infrastructure from her NIH- funded research to advance this time-sensitive, high-impact work in a manner that is scientifically significant, clinically innovative, mechanistically plausible, and feasible for completion within the allotted time frame and budget. Our central hypothesis is that phenotypic characterization of INOCA patients beyond body mass index will yield important insights to understanding and treating this understudied cardiometabolic condition. We will investigate the following specific aims: (1) to comprehensively assess novel body composition metrics across lean and ectopic adipose tissue depots and identify their relationship to CMD in INOCA patients using multimodal imaging with PET/CT, (2) to identify cardiometabolic pheonotypes in INOCA patients associated with major CVD events, including death and hospitalization for MI and HFpEF, and (3) to evaluate the impact of serial clinical weight loss interventions (GLP-1 agonist and bariatric surgery) on body composition, coronary microvascular function, myocardial strain and cardiorespiratory fitness in patients with INOCA and severe obesity. By rigorously characterizing body composition, CMD and HFpEF risk in INOCA, the proposed aims will definitively clarify our understanding of this understudied condition overrepresented in women and tailor novel discovery to exert a sustained, powerful influence on obesity/cardiometabolic health research.

NIH Research Projects · FY 2026 · 2025-09

Project Summary Neutrophils are major players in the innate immune system, known for their role in fighting infections by engulfing and destroying invading pathogens, including those in the lungs. Neutrophil heterogeneity is a key component in innate immune regulation. Distinct mature neutrophil subpopulations, defined by their signature gene expression profiles, phenotypes, behaviors, and functional states, exist even prior to encountering pathogens. Understanding the unique features and origins of these functional subpopulations will enable the effective and safe manipulation of their specific functions for personalized medicine. The objective of this proposed project is to investigate the origin and characterize the functional state of the lung interstitial neutrophil (LIN) subset. Preliminary scRNA-Seq analysis revealed a tightly regulated neutrophil reprogramming trajectory during lung infection and inflammation, based on gene expression patterns. The preliminary studies identified the functional heterogeneity of neutrophils across three different lung compartments: the vasculature, the interstitium, and the alveoli, and discovered that neutrophils lodged in the interstitium for an extended period before migrating to the alveoli. Based on these findings, it was hypothesized that transcriptional reprogramming leads to the formation of a specialized LIN subset defined by its unique gene expression profile. These neutrophils are highly specialized, with significant bactericidal activity, making the lung interstitium a primary site for bacterial elimination. Accordingly, expanding the LIN population could be a viable therapeutic strategy for enhancing neutrophil-mediated host defense, while potentially detrimental in sterile inflammation-induced acute lung injury. To advance the understanding of the function, fate, pathophysiological role, and origin of LINs and explore their therapeutic potential, three specific aims will be investigated: Aim 1 will characterize the functions and fate of LINs. In addition, neutrophil- mediated bacterial killing in the interstitium will be visualized and confirmed by fluorescent imaging. Aim 2 will elucidate the pathophysiological role of LINs in lung infection and inflammation. The LIN population will be expanded by inhibiting CCR2-mediated neutrophil transepithelial migration, and its effect on host bactericidal activity and lung injury will be tested in a neutropenia-related bacterial pneumonia model and an acid aspiration-induced acute lung injury (AA-ALI) model. Aim 3 will further investigate the microenvironment- induced transcriptional reprogramming that confers specialized functions to LINs. Additional scRNA-Seq analyses will be performed to gain a deeper understanding of neutrophil reprogramming in the interstitium and to reveal potential temporal and stimulus-specific reprogramming schemes. Together, the results from this study will establish LINs as a specialized neutrophil subpopulation with unique phenotype and function, and as a novel therapeutic target for treating lung infections and inflammation.

NIH Research Projects · FY 2025 · 2025-09

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality for the more than 530 million adults with type 2 diabetes (hereafter diabetes) worldwide. Moreover, diabetes is increasingly recognized as a major public health threat worldwide: for instance, as of 2021, over 90 million adults in India, Mexico, and similar settings were estimated to have diabetes. Recognizing this, the World Health Organization (WHO) and national governments have newly committed to the Global Diabetes Compact targets, which aim to ensure that 80% of people with diagnosed diabetes achieve glycemic and blood pressure control, and 60% receive a statin. However, investments in the diabetes care continuum required to achieve these targets remain inadequate, in part because the health benefits and cost-effectiveness of these investments have not been clearly demonstrated. The primary objective of this application is to assess the impact of improving CVD care for adults with diagnosed diabetes in these diverse global settings on clinical outcomes, cost-effectiveness, and health equity. This project is led by Dr. Jennifer Manne-Goehler, an accomplished Early-Stage Investigator with expertise in global diabetes, and an interdisciplinary team of experts in microsimulation modeling and global CVD epidemiology, including: Drs. Kenneth Freedberg, Mark Siedner and Oyere Onuma from Massachusetts General Hospital, Pooyan Kazemian from Case Western University, and David Flood from University of Michigan. In this proposal, we will first develop the PREDICT-DM Global simulation model of CVD in adults with diabetes and populate it with empiric data from across several high-prevalence settings, leveraging a previously validated pilot model. Next, we will use the model to evaluate the clinical impact, costs, and cost-effectiveness of strategies to scale-up established therapies for glycemia, blood pressure, and lipids on CVD outcomes for adults with diagnosed diabetes in each of these countries under different scenarios. Third, we will investigate the clinical impact, costs, cost-effectiveness, and equity implications of introducing novel therapies such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) on CVD outcomes in these same populations. By bringing together an outstanding, experienced, interdisciplinary team, we will create a highly adaptable and durable platform for developing and informing strategies to strengthen comprehensive CVD care and improve CVD outcomes for adults with diabetes globally over the next decade.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Alzheimer’s disease (AD) and related dementias (ADRD) pose significant challenges with a growing societal impact. Addressing these challenges requires comprehensive research into the neurobiology of the diseases, leading to innovative biomedical concepts, approaches, and molecular targets. A central factor in these disorders is the protein tau, whose misregulated homeostasis, aggregation, and intercellular spread contribute to AD, Frontotemporal dementia (FTD), and other tauopathies. Tau-containing neurofibrillary tangles (NFTs) from AD brains are known to contain RNA, and it is proposed that tau-RNA interactions may facilitate tau aggregation and modulate neuronal vulnerability to stress. However, the specific RNA species involved in tau pathology remain unidentified. Our data suggest a novel class of small RNA transcripts—tRNA-derived fragments (tRFs)—that accumulate in AD, potentially binding tau and promoting its misfolding and aggregation. Regulated by disease-related neuronal stress, tRFs are enriched in extracellular spaces and body fluids, including cerebrospinal fluid (CSF), and can be taken up by recipient neurons. Our research aims to investigate the role of specific tRFs in tau aggregation, pathology propagation, and neurodegeneration in ADRD through the following Specific Aims. Specific Aim 1: Characterize the small RNA landscape, with a focus on tRFs, at different stages of AD pathology using an optimized RNA sequencing platform. Examine the RNA binding capacity of intracellular and extracellular tau variants and mutants using human induced pluripotent stem cell (iPSC)-derived neurons and rodent primary neurons. Identify tRFs within pathological tau aggregates and visualize their colocalization with tau pathology in human AD brains. Specific Aim 2: Investigate the impact of selected tRFs and tRF-enriched extracellular complexes on tau homeostasis and pathology using gain- and loss-of-function approaches in neuronal cell models. Specific Aim 3: Examine the effects of specific tRFs on tau pathology and behavioral phenotypes in WT mice and a humanized Tau P301S/PS19 mouse model of tauopathy and neurodegeneration. Assess neuroprotective effects of targeting specific tRFs in the brain. This collaborative R01 project seeks to unravel the complex molecular mechanisms underlying ADRD and explore the cellular and extracellular biology of these disorders. Findings may reveal a new class of potential therapeutic targets and biomarkers.

NIH Research Projects · FY 2025 · 2025-09

Depressed patients who fail to respond to >2 antidepressants are burdened by treatment-resistant depression (TRD) and endure lengthy trial-and-error attempts on multiple treatment regimes while at risk for poor outcomes. Clinicians lack decision support tools to select initial or subsequent TRD treatments in part because predictors of treatment response are considered static (time-fixed), despite varying over time. Clinical decision support systems (CDSS) called for in MH-25-190 need dynamic treatment regimes (DTRs): sequences of rules that dynamically update response predictions as information accumulates. We will achieve this with: 1. Electronic Health, Patient-Reported Outcome, and Digital Biomarker Data on >10,000 TRD Patients Annually; 2. Advanced Causal Inference and Target Trial Emulation to Control for Time-Varying Confounding; and a 3. Sequential Multiple Assignment Randomized Trial (SMART) to Optimize Dynamic Decision Support Rules in: Aim 1. Pipeline to Identify Dynamic Treatment Regimes (DTRs) for Clinical Decision Support Systems TRD regimes received by >10,000 TRD outpatients in >85,000 visits annually, will include: medication management (e.g., combining, switching, or augmenting antidepressants); rTMS; psychotherapies; and esketamine or ketamine. We will create a pipeline to: a) generate features from electronic health, patient-reported outcome, and raw digital biomarker data; b) filter features; c) control for time-varying confounding with advanced causal inference; d) evaluate dynamic prediction rules to classify patients according to treatments they are likely to benefit from; and e) empirically design a CDSS with optimal DTRs for TRD. Aim 2. Target Trial Emulation (TTE) of the Clinical Decision Support System (CDSS) for TRD Although milestones (e.g., AUROC> .8) will be used to analytically validate models in Aim 1, they cannot estimate clinical benefits of using a CDSS to select treatments v. usual trial-and-error care. Before committing to a randomized trial, target trial emulation (TTE) is a gold standard way to first use observational data to evaluate comparative effectiveness. We will employ TTE to compare using DTRs in a CDSS to select TRD treatments v. usual trial-and-error care; milestones from our TTE (e.g., Cohen’s d for CDSS-informed care >.5) will determine if we proceed with user-centered design of a CDSS and testing in the randomized effectiveness trial in Aim 3. Aim 3. Effectiveness Trial of Clinical Decision Support System (CDSS)-Informed vs. Usual TRD Care We will conduct an effectiveness trial in which 1,000 TRD patients are randomized to a CDSS with optimal DTRs from a SMART v. usual trial-and-error care. On-line (live and in real-time) reinforcement learning models will use past and current tailoring variables to predict an individual’s response to treatments in the next interval, and also adapt based upon prior participants’ responses. We will compare both arms on distal outcomes (i.e., ER visits or hospitalizations for depression; all-cause and suicide deaths), and work with NIMH/FDA to ensure the trial serves as a “Real-World Performance” review for FDA Software as a Medical Device designation.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Millions of adults experience circadian rhythm disruption daily due to shift work, transmeridian travel or irregular sleep schedules, leading to short-term symptoms of jetlag as well as longer-term adverse health outcomes. While effective interventions to treat circadian disruption using for example light exposure or exogenous melatonin are available, these typically aim to resynchronize only centrally controlled circadian rhythms. In contrast, circadian disruption of peripherally controlled rhythms and interventions to resynchronize peripheral circadian rhythms are underdeveloped. The disruption of peripheral circadian rhythms may underlie the short- term gastrointestinal symptoms many people experience with transmeridian travel or rotating between day and night shifts, and chronic disruption of these peripheral circadian rhythms may be a significant risk factor for developing cardiometabolic disease. Mathematical models of the human circadian system have played an important role in developing sleep- and circadian-informed lighting interventions for mitigating symptoms of central circadian rhythm disruption, but until recently there has not been sufficient evidence to develop and validate models for peripheral circadian rhythms. Emerging evidence from our group and others indicates that while light remains the primary synchronizer of central circadian rhythms, meal timing may be the primary synchronizer for peripheral circadian rhythms including those of circulating serum lipids in humans. For example, we have identified robust circadian rhythmicity in circulating serum cholesterol and preliminary findings from our current NHLBI-supported study indicates that cholesterol phase resets in response to changes in meal timing, even in the presence of circadian photobiologically inert dim light exposure. Given the utility of existing mathematical models to design sleep- and circadian-informed lighting interventions for central circadian rhythms, we propose in this project to take a data-driven approach that leverages our current mathematical framework— the Kronauer-Jewett-St Hilaire (KJS) model of the effects of photic and non-photic stimuli on the human circadian system—to develop and validate a novel mathematical model of the effect of meal timing on peripheral circadian rhythms. We will use the existing mathematical framework and systematic modeling approaches to incorporate cholesterol phase as a peripheral circadian rhythm, add meal timing as an additional non-photic stimulus in the model, and use data from multiple studies collected under highly controlled laboratory conditions to refine and validate the model against experimental cholesterol phase response curves to meal timing. We expect the mathematical model of the peripheral circadian system that results from this work will be used in tandem with the existing mathematical model of the central circadian system as foundational tools for developing and testing multifaceted interventions for comprehensively treating both peripheral and central circadian disruption that occurs during shift work, transmeridian travel, and irregular sleep schedules.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Abstract: The skin is a barrier tissue that is impacted by all types of external radiation events and is accessible to non- invasive testing. Tape stripping of the skin is an effective, well established, and non-invasive method for sampling both protein and RNA biomarkers in human skin. We have developed a model of studying radiation injury in human skin by irradiating living human skin grafts carried by immunodeficient NSG mice. Our model recapitulates both the early inflammatory and late fibrotic changes in skin observed in patients after radiation exposure. We present pilot spatial profiling and immunostaining data demonstrating that superficial keratinocytes, the cell population sampled by non-invasive tape stripping, upregulate RNA and protein biomarkers within 24 hours of radiation exposure and that different biomarkers have the potential to discriminate between 1, 2 and 5 Gy radiation. In this proposal, we will identify optimal keratinocyte biomarkers of radiation exposure and develop a point-of-care test to measure them using non-invasive tape stripping. In Aim 1, we will identify, validate and measure the expression kinetics of keratinocyte biomarkers of radiation exposure (0, 1, 2, 5 Gy) in human skin grafts carried by NSG mice. Xenium 5000 plex spatial transcriptional profiling will be used to identify candidate biomarkers (Aim 1A), followed by single cell proteomic measurement of candidate biomarkers using cyclic immunofluorescence (CyCIF) in both discovery and validation sample cohorts (Aim 1B,C). The kinetics of protein biomarker expression will then be evaluated via CyCIF on days 1, 2, 3, 5, and 7 after 1, 2, or 5 Gy irradiation (Aim 1D). In Aim 2, we will use NSG mice grafted with neonatal foreskin and skin obtained from aged patients (>65 years) to study the utility of identified biomarkers in pediatric and aged individuals. In Aim 3, we will develop and test a point-of-care test to measure biomarkers using non-invasive tape stripping of the skin. These studies will generate validated, human cutaneous biomarkers of radiation exposure and a non-invasive test to measure them that is immediately applicable to the care of humans exposed to radiation.