Brigham And Women'S Hospital

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Malignant glioma, particularly glioblastoma (GBM), remains among the most lethal forms of cancer and represents a significant unmet need in current medicine. The median survival of GBM patients is approximately 15-20 months with highly aggressive standard care, and the five-year survival rate is about 5%. There are no effective therapies for the disease. Over the years, we accumulated evidence that GBM growth and invasiveness are closely regulated by microRNAs, small regulatory molecules that control gene expression and strongly contribute to gliomagenesis. We demonstrated that this class of molecules holds great promise as therapeutic targets for neuro-oncology. Our work led us to focus on miR-10b, a unique growth and invasion-promoting miRNA and common molecular target for GBM in adults (otherwise a highly heterogeneous class of brain malignancies). We identified miR-10b, essential for glioma growth, as a top and common therapeutic target for GBM. Inhibition of miR-10b using different strategies reduced tumor growth in all tested glioma cell and animal models. CRISPR/Cas9 gene-editing of miR-10b emerged as the most potent therapeutic strategy in mice, and it holds great promise for GBM patients. We developed potent and safe lipid nanoparticle (LNP) -based miR-10b editing formulation as a new class of precision medicine for GBM. Our objective is to advance this miR-10b editing drug (called miRTED) into a “first-in-human” clinical trial in subjects with GBM. The Specific Aims of this project are, in UG3 component (Discovery phase): 1) Finalize the efficacy of miRTED administration using diverse orthotopic GBM models, 2) Assess the toxicity and off-target effects of miRTED administration using human and rodent neuroglial cells, brain organoids, and mouse models to establish dosing guidelines, and during UH3 component (Development phase): 3) Partner with BPN team and selected contract research organization to manufacture preclinical and then GMP-grade clinical lots of the LNP, 4) Partner with BPN team and selected contract research organization to conduct IND-enabling mouse toxicology and biodistribution studies, and 5) Finalize the writing and filing of the IND application with the FDA. Due to glioma “addiction” to miR-10b, the new strategy is expected to be highly efficacious for most, if not all, GBM patients despite the heterogeneity of the disease. This approach is principally different from other gene therapies proposed for the GBM- that all target only a subpopulation of patients. It can be used in combination with, or ultimately replace, the current standard care. In addition, the LNP formulations developed in this project could provide a platform technology for precision medicine targeting other tumor vulnerabilities. Notably, the recent success of COVID mRNA vaccines and in vivo gene editing trials provide POCs for the efficacy, safety, and scalability of mRNA/LNPs and CRISPR/Cas9 components in humans.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Genetic factors have been shown to contribute to COPD susceptibility, and genome-wide association studies (GWAS) have identified 82 loci associated with COPD risk. We have previously found associations of many COPD risk-related GWAS-identified variants with alternative splicing; specifically, we have observed that genetically driven splicing of genes including NPNT, FBXO38, and BTC contributes to COPD risk. However, common variants associated with disease have modest effects on disease risk, and the genetic loci identified to date through GWAS explain only 5-10% of the heritability of COPD or measures of lung function. While GWAS effectively identifies common genetic variants associated with disease, rare variants such as those in alpha-1 antitrypsin deficiency, cutis laxa, cystic-fibrosis transmembrane conductance regulator and telomere- related genes also contribute to COPD risk, as has been found for other complex diseases. Recent large-scale studies using genome-wide and exome sequencing have identified vast numbers of novel variants and have provided an opportunity to investigate the impact of rare coding variants on complex human traits and diseases. However, a major challenge in the interpretation of rare variants lies in the currently limited ability to infer the functional and clinical impact of those variants. As for common variants, it is likely that many rare variants influence the regulation and expression of causal genes. Variants that alter splicing hold a particular interest, as they can lead to drastically altered RNA isoforms, such as through frameshifts or loss of functionally important domains. Our central hypothesis is that rare genetic variants contribute to COPD by causing aberrant splice events with large effects. This work will build directly from Dr Saferali’s (PI) K01-funded project that identified common genetic variants that contributed to COPD by modulating transcriptional splicing. In this proposal we will utilize resources from two large cohort studies: the Lung Tissue Research Consortium (LTRC) dataset and the Genetic Epidemiology of COPD Study (COPDGene). In Aim 1 we will discover outlier splicing events using RNAseq data from LTRC lung tissue and COPDGene whole blood, identify rare variants causal for those events, and test for association between those variants and COPD and related phenotypes. In Aim 2 we will use long read sequencing to identify full length isoform sequences in individuals with outlier splicing, followed by prediction of the protein-level impact of the splice event. In summary, this proposal from a productive early-stage investigator leverages data and skills acquired during the PI’s K01 funding period and substantial resources from ongoing cohort studies to explore a new approach to identify genes and mechanisms that contribute to COPD and related phenotypes. Importantly, this work proposed will yield urgently needed insights into the role of rare variants in COPD risk while also generating important preliminary data to form the basis of the PI’s future independent research program.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT The R03 application builds upon Dr. Yun’s K08-funded study, which investigated how hedgehog interacting protein (HHIP) deficiency contributes to lymphocytic inflammation in chronic obstructive pulmonary disease (COPD). Through that work, we identified unique CD8+T cell populations in both a murine model and human COPD lungs. In this proposal we will focus on a specific CD8+T cell subset expanded in mild to moderate (early) COPD and investigate its contribution to COPD development and progression. By leveraging longitudinal cohorts and single-cell immune profiling, we will determine 1) whether this subset is associated with COPD development and progression, and 2) the clonal and antigenic drivers that underlying its expansion. Our emphasis on defining the transcriptomic, clonal, and antigenic properties of this CD8+T cell subset in COPD will advance our understanding of inflammatory pathogenesis and potentially provide a foundation for novel therapeutic strategies aimed at slowing disease progression.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Lung function (LF) decline, a key indicator of respiratory health, is closely linked to age-related diseases, driving up healthcare costs and reducing quality of life. Understanding and mitigating LF decline is therefore essential. Aging, influenced by cellular senescence, inflammation, and oxidative stress, plays a central role in chronic disease progression. However, the molecular mechanisms underlying lung aging and disease susceptibility remain poorly understood. Inflammation and oxidative stress accelerate LF decline, while miRNAs and metabolites serve as key regulators, shaping both aging and disease trajectories. Clustering longitudinal lung function (LLF) data helps to identify patient subgroups with distinct disease patterns, enabling risk prediction and deeper insights into disease mechanisms. The central hypothesis of this proposal is that LF trends over time can cluster individuals, showing differences in epigenetic aging and predicting health outcomes, with multi-omics data uncovering the association between poor LF and accelerated aging. The overall objective of this proposal is to 1) develop and validate LLF based SpiroClusters in two large cohorts with electronic medical records (EMR) data and investigate associations between SpiroClusters, epigenetic age acceleration (EAA), and lung health outcomes; 2) identify shared and unique molecular signatures between SpiroClusters, LF decline and epigenetic aging rate (EAA) to reveal the molecular mechanisms associating worse LF trajectories to accelerated aging; 3) Develop a Molecular Knowledge Graph (MKG) of lung aging as a comprehensive resource for scientific community with multiple utilities, including biomarker identification, therapeutic target prioritization, and decoding mechanism of lung aging. Dr. Rinku Sharma, a bioinformatician, aims to become an independent data scientist specializing in multi- omic approaches to aging and lung disease. Her career plan focuses on: (1) deepening her understanding of aging and related lung diseases; (2) expanding her statistical skills, including integrative omics and longitudinal lung function clustering; (3) refining her skills in handling, QC, and integrating diverse omics data, such as epigenetics and metabolomics; and (4) enhancing her skills in study design, mentorship, and research ethics/communication. Dr. Sharma's strong quantitative and methodological background, combined with the support from a diverse and world-class mentoring and advisory team from the Channing Division of Network Medicine at Brigham and Women’s Hospital and Harvard Medical School, has well prepared her to complete the aims of this proposal, and establish a successful, independent research career.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT The global population is aging rapidly, with the number of people over 65 expected to double by 2050. Aging alters hematopoietic stem cells (HSCs), leading to increased inflammation, immune dysfunction, and clonal hematopoiesis. These changes have been linked to hematological disorders, cardiovascular disease, and other age-related conditions. Dissecting the contribution of human HSC heterogeneity to these disorders has been accelerated by single-cell RNA-sequencing and the development of new algorithms to derive of biologically meaningful insights. These algorithms include consensus non-negative matrix factorization (cNMF) and CellAnnoTator (*CAT), which aim to identify consensus gene expression programs that shape cellular heterogeneity across datasets. However, these algorithms have not been applied to human HSC aging, and the circuitry that controls their role in aging and disease remains poorly understood. There is a here is a critical need to identify the molecular programs that drive age-associated changes in human HSCs. The long-term goal is to mitigate age-related immune dysfunction and its associated diseases. The central hypothesis is that inflammatory signaling is a principal driver of human HSC heterogeneity and that AP-1 factors define an HSC subset that expands with age. To test this hypothesis, the investigators will pursue two specific aims: 1) Identify age-associated changes in HSCs across eleven existing datasets, and 2) Determine how consensus gene expression programs shape HSC heterogeneity and relate to aging. For Aim 1, the working hypothesis is that aging HSCs exhibit consistent gene expression changes, including AP-1 activation in a subset that expands with age. Using publicly available datasets, the investigators will identify conserved gene expression and transcription factor activity changes and leverage single-cell data to quantify an aging-associated subset of inflammatory HSCs. For Aim 2, the working hypothesis is that applying cNMF and *CAT within a unified analytical framework will identify biologically meaningful gene expression programs that underlie HSC heterogeneity, including inflammatory pathways linked to aging. The investigators will identify consensus gene expression programs in HSCs, assess their association with age and inflammation, and develop an R-based computational pipeline for broader community use. The expected outcome is the discovery of programs and genes, led by AP-1, that shape heterogeneity of human HSC aging across datasets. The proposed research is innovative because it shifts from evaluating the human HSC compartment as a whole to linking a distinct HSC subset to aging and because it applies an advanced analytical framework to identify consensus gene expression programs shaping HSC heterogeneity. The significance of this research is that it will establish a foundation for predicting how HSC aging impacts immune fitness, systemic inflammation, and cardiovascular risk.

NIH Research Projects · FY 2026 · 2026-04

Abstract The overarching goal of this project is to elucidate the role of biological sex in modulating the adverse metabolic effects of circadian misalignment, with the ultimate aim of designing sex-specific interventions to mitigate health risks associated with night shift work. Night shift work, prevalent in both male and female workforces, significantly increases the risk of metabolic disorders, including obesity and diabetes. A key contributor to these risks is circadian misalignment—misalignment between behavioral/environmental cycles and the body’s internal circadian system—which disrupts energy balance and impairs glucose tolerance. Despite established sex differences in human circadian physiology and metabolism, few experimental studies have explored whether these differences influence the metabolic consequences of circadian misalignment. Our pilot data from controlled laboratory studies provide proof-of-principle evidence of sex-specific effects. Acute circadian misalignment disrupted energy balance through distinct mechanisms: in women, it decreased satiety and increased hunger hormones, while in men, it elevated cravings for hyperpalatable foods. Preliminary findings also suggest that men are more susceptible to glucose intolerance under circadian misalignment compared to women. To build on this foundation, our proposed study addresses key limitations of prior work and systematically tests the following hypotheses: (Aim 1) Circadian misalignment leads to more adverse changes in appetite-regulating hormones in women than in men. (Aim 2) Circadian misalignment results in greater impairment of glucose control in men compared to women. (Aim 3A) Circadian misalignment increases homeostatic appetite in women and hedonic appetite (cravings for hyperpalatable foods) in men. (Exploratory Aim 3B) Circadian misalignment more adversely impacts food-related neurocognitive control (e.g., impulsivity and motivation) in men. (Exploratory Aim 3C) Circadian misalignment increases overall energy intake in women and promotes higher carbohydrate and saturated fat consumption in men. This study utilizes a balanced parallel group design (men vs. women), with each participant serving as their own control in a randomized, cross-over protocol (circadian alignment vs. circadian misalignment). Aims 1, 2, and 3A&B will be conducted under highly controlled laboratory conditions with energy-balanced diets. Aim 3C will evaluate ad libitum food intake on the final study day to assess potential implications without confounding other measurements. By uncovering sex-specific vulnerabilities to circadian misalignment, this project will provide novel insights into the physiological mechanisms driving shift work-related health risks. These findings hold broad implications for designing tailored shift work schedules, developing sex- specific interventions, and addressing sex disparities in clinical care, ultimately improving the health and well- being of millions of shift workers worldwide.

NIH Research Projects · FY 2026 · 2026-03

Abstract Musculoskeletal (MSK) disorders affect approximately 126.6 million adults in the United States, accounting for more than half of the adult population. The development of disease-modifying drugs (DMDs) for these conditions remains particularly challenging due to subjective clinical assessments, the absence of reliable animal models that closely mimic human pathology, and the high costs associated with large-animal studies. MSK disorders are influenced by various factors, including environmental exposures, aging, hormonal changes, degenerative diseases, and injuries, impacting individuals across all demographics. While surgical interventions are sometimes an option, they often have high failure rates, leading to disability and progressive tissue deterioration. The financial burden is immense, with U.S. healthcare costs related to MSK conditions exceeding $400 billion annually. To overcome these challenges, innovative preclinical platforms incorporating human cells and tissues are crucial for generating reliable data to support DMD development. Our team consists of experts with a strong track record in bioengineered systems that accurately replicate human MSK structures and functions. Leveraging our extensive experience with stem cells, organoids, and advanced in vitro culture platforms, we propose the establishment of an MSK New Approach Methodologies (NAMs)Technical Development Center (TDC) to drive the innovation of combinatory physiological models for muscle, cartilage, tendon, and intervertebral disc research. Through this initiative, we will investigate MSK pathologies—including mechanical overloading, inflammation, and injury—while considering key influences such as environmental exposures, aging, and hormonal effects. Additionally, by collaborating closely with the Consortium Steering Committee, the Validation and Qualification Network (VQN), and the NAMs Data Hub and Coordinating Center (NDHCC), the MSK NAMs developed through this effort will be widely accessible to a broad range of downstream users.

NIH Research Projects · FY 2026 · 2026-03

In the epidemic of social isolation affecting today’s society, stroke survivors are particularly vulnerable. After stroke, social isolation has adverse biological and psycho-social effects, which can be prevented. Therefore, increasing social connection has the potential to be a powerful strategy for enhancing stroke recovery outcomes. Developing effective interventions, however, necessitate accurate and high-fidelity measurement of social life changes after stroke, and knowledge of how these changes relate to patient characteristics and recovery trajectories. Traditional research methods rely on self-report surveys, which are subjective, retrospective, and cannot be completed in up to 45% of patients due to cognitive and language deficits. Therefore, there is gap in measurement of social connection that limits the design of interventions. In response, we developed SocialBit, an artificial intelligence algorithm that operates on a smartwatch and utilizes ambient audio features to detect minutes of social interaction without storing any raw audio data. It provides an objective, continuous, inclusive, and high-resolution picture of social life changes after stroke, which can inform decision-making around when and how to intervene in this at-risk population. We created and validated SocialBit specifically for stroke survivors, taking into account cognitive, physical, and language variations. Our preliminary data show that SocialBit measures an important aspect of patients’ social connection: time spent interacting. However, our studies to date focus on the context of the hospital. The goal now is to deploy SocialBit in patients’ natural, everyday environments, which will be the first study of objective social connection of stroke survivors. We propose a study of two hundred (N = 200) patients with ischemic stroke who will wear a SocialBit smartwatch for 3 months after hospitalization. Our central hypothesis is that there will be discernable trajectories of post-stroke social life related to stroke and contextual factors that predict cognitive and physical outcomes, which are ideal targets for future interventions. The study aims are to 1) Characterize patients’ social interaction trajectories for the first 3 months after ischemic stroke in relation to important stroke characteristics and contextual factors; 2) Examine the bidirectional associations between participants’ social interaction, cognitive, and physical functioning over the first 3 months following ischemic stroke; and 3) Through qualitative inquiry, determine the social interaction mechanisms that may be leveraged by SocialBit to improve stroke recovery. We have assembled a multidisciplinary team with expertise in stroke, artificial intelligence, mobile sensing, mixed methods, and social connectedness to execute this project. Achieving these aims will provide foundational insights into quantifying social connection for stroke survivors. Moreover, this study represents a significant advancement by employing a direct, continuous, and scalable in-vivo mobile sensing method for measuring social connection. The acquired data will set the stage for testing "pro- connection technology" to improve quality of life for stroke survivors.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY (See instructions}: Though cardiovascular disease (CVD) management has advanced, CVD remains the leading cause of premature death worldwide. As age remains the dominant factor in CVD risk and the population ages, the poorly understood age-related factors promoting CVD risk require urgent investigation. This proposal uses functional human genomic and multi-omics modifier analyses with the human specimen to investigate the mechanistic links between clonal hematopoiesis of indeterminate potential (CHIP) and CVD toward improving clinical management. CHIP is common in elders (~1 in 10 among >70 years), and recent data establish coronary artery disease (CAD), a primary cause of CVD, as the primary cause of the increased mortality in those with CHIP. With the discovery in N-37K and replication in N-5K, preliminary data show that SNPs on chromosome 1 0q23.32 increase the CAD hazard among those with CHIP 10-fold but are not associated with CAD among those without CHIP. Downstream analyses showed the potential role of CPEB3, which modulates the IL-6 signaling pathway, in line with the previous studies showing the importance of the IL-6 pathway for CAD development in CHIP carriers. However, the exact mechanisms are yet to be elucidated. Further genomic and functional molecular analyses would identify novel CHIP-specific mechanisms in CAD pathogenesis and lead to CAD prevention strategies among CHIP carriers with the most robust preclinical evidence in humans. The aims of this proposal will: discover the further germline genetic predisposition that induces CHIP-related CVD with an increased sample size (-575K: >10-fold from the preliminary study) to construct CHIP specific polygenic interaction risk score (PIRS) for CAD, which stratifies the risk of CVD in CHIP carriers (Aim 1 and 2), prioritize causal mechanisms for CHIP-related CAD with the integration of genomic data and multi-omics data (Aim 1), and dissect the molecular mechanisms for CHIP-related CAD combining population genetics and analyses of human specimens (Aim3). Successful completion of the aims will pave the way for cardiovascular risk management of CHIP carriers by (i) improving risk stratification and (ii) improving our understanding of the causal underpinnings of CAD and CHIP.

NIH Research Projects · FY 2026 · 2026-03

Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare inherited neurodegenerative disease caused by expansion of a glutamine-coding CAG repeat in the Atrophin-1 (ATN1) gene. The role of ATN1 in the adult central nervous system (CNS) is currently unknown. However, the clinical manifestations of DRPLA lead to a constellation of symptoms that are inversely correlated to CAG-expansion (CAGEX) size, with younger individuals typically carrying the largest number of CAG repeats, experiencing the most severe disease burden. Importantly, young patients with DRPLA face poor cognitive outcomes, including developmental delay, with a prevalence of high-frequency, drug-resistant seizures and epilepsy diagnosis. The mechanisms leading to increased neuronal hyperexcitability and seizure risk in DRPLA patients are presently unknown. Thus, preclinical humanized in vitro and in vivo models of ATN1 CAGEX represent a novel platform to expediently assess innovative therapies for symptomatic seizure control and disease modification. Further, these models allow exquisite translational fidelity to define how ATN1 mutations lead to neuronal hyperexcitability. Indeed, our labs have recently identified both an increased neuronal excitability using a versatile patient-specific induced pluripotent stem cell (iPSC)-derived in vitro system and an altered seizure threshold in vivo using a novel mouse model expressing a humanized ATN1 CAG repeat expansion. In vitro studies in human patient iPSC-derived cortical neurons using live-cell calcium imaging and multi-electrode array recordings demonstrate altered neuronal network activity by manifesting increased calcium spike amplitude and hypersynchronization, both characteristics simulating epileptiform-like phenotypes. Notably, we have preliminarily demonstrated that neuronal hyperexcitability (in vitro) and seizure threshold (in vivo) can be rescued with exogenous administration of investigational ATN1- silencing antisense oligonucleotides (ASOs). Further, circadian behavior of ATN1 CAGEX mice administered the investigational ASO were normalized, indicating a disease-modifying effect in this clinically relevant rodent model of DRPLA. The present proposal thus aims to expand these pilot studies to address the mechanism behind ATN1 CAGEX-dependent spontaneous seizure risk and neuronal hyperexcitability in vitro and in vivo, and to further define the potential seizure-modifying effects of ASO infusion in the early disease course. Aim 1 will utilize patient iPSC-derived neuro-glial model to characterize the physiological and molecular mechanism of the DRPLA epileptiform and asses ASO efficacy in phenotypic rescue. Aim 2 will then expand on these in vitro studies to establish whether Atn1 CAGEX mice exhibit spontaneous recurrent seizures and define the degree to which an investigational ASO infusion influences the occurrence of these events and improves neuropathological burden. This study will deepen our understanding of the impact of ATN1 CAGEX on pathological neuronal activity and seizure risk while establishing proof-of-principle evidence that ASO intervention is a disease-modifying strategy for DRPLA, a progressive myoclonic epilepsy syndrome with no palliative or curative options.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT: Sepsis results from a dysregulated host response to infection leading to life-threatening organ dysfunction. It is a complex and dynamic disease process, and a leading cause of morbidity and mortality in intensive care units (ICUs). Due to the therapeutic challenges of patients with sepsis, and the fact that management remains predominantly supportive, there is an undeniable need to develop new treatment strategies for sepsis. New advances being explored include cell-based therapies. For more than 25 years my laboratory has explored the pathobiology of sepsis, and related organ injuries, including the lung. Our approach is to investigate mechanisms of disease, starting at the cellular level in vitro and translating these findings into models of disease ex vivo and in vivo. To complement our work further in sepsis, with an interest in therapy, we became interested in stem/stromal cells. My laboratory has explored the use of mesenchymal stem/stromal cells (MSCs) for therapeutic intervention in pre-clinical models of sepsis and lung injury. We investigate mechanisms responsible for the biological activity of MSCs, including paracrine actions via their conditioned medium and the impact of MSC-derived extracellular vesicles (EVs) and their cargo (miRNAs). To advance our understanding of cellular therapy for sepsis, we recently began to explore a new source of cells – placenta-derived trophoblast stem cells (TSCs). Our laboratory was the first to isolate murine (m) TSCs, using CD117 as a cell surface marker of stem/progenitor cells. Beyond paracrine actions, these cells can engraft and differentiate into parenchymal cells. We now propose to advance our investigation of TSCs harvested from human(h) term placentas. hMSCs are immune evasive, and hTSCs are immune privileged, allowing the use of both cells for allogeneic therapy. We will investigate hMSCs and hTSCs to modify the pathobiology of sepsis and provide insight into the immune response to eradicate microbes, resolve inflammation, and decrease organ injury along with promoting repair. Sepsis and organ injury, such as acute respiratory distress syndrome (ARDS), are very heterogeneous clinical processes, thus targeting a specific biological pathway is challenging. We propose that viable therapeutic cells will sense the underlying septic environment, and respond accordingly with varied paracrine actions. Plasma and immune cells from patients with sepsis ± ARDS, compared with ICU control (non-infected) patients, will allow us to explore a personalized approach using hMSCs and hTSCs. Moreover, due to differences that exist between human and mouse lungs, we propose to evaluate the actions of hMSC and hTSCs using human lung organoids and precision-cut lung slices (PSLS) as human models of lung/alveolar injury, and transcriptomic approaches to identify pathways critical for disease modification. Thus, our vision is to advance the insight into therapies for sepsis using hMSCs and hTSC, and that using human models of disease in vitro, ex vivo, and with confirmation in a pre-clinical model of pneumosepsis will provide insight into critical sepsis pathways and advance our approach to the therapy of sepsis and ARDS.

NIH Research Projects · FY 2026 · 2026-03

Peripheral artery disease (PAD), affecting over 200 million people globally, often advances to chronic limb- threatening ischemia (CLTI), characterized by chronic ischemic rest pain with high risk for amputation and heightened mortality. CLTI is the leading cause of amputations in adults, but there are no medical therapies available that generate a long-term clinical benefit. Recent clinical findings suggest that in CLTI, vascular growth factor overexpression acting on cells in ischemic skeletal muscle result in the formation of abnormally enlarged capillaries with decreased blood transit time and capillary detachment from skeletal muscle fibers. We hypothesize that future therapeutics in CLTI must address microvascular abnormalities to form stable, functional capillaries to improve perfusion to the ischemic limb. Non-coding RNAs (both microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)) are an emerging class of regulators of epigenetic modifiers, RNA, or protein-coding genes that has garnered attention for impacting diverse biological processes relevant to ischemic injury and for their therapeutic potential. However, the identity and roles of specific ncRNAs involved in CLTI are not well defined. Our published and preliminary studies reveal how ncRNAs can control stage-specific aspects of angiogenic growth, migration, sprouting, and permeability in CLTI. Furthermore, we have elucidated ncRNA functions in vivo and translated these findings into novel therapeutic approaches, including the demonstration that local delivery of ncRNAs potently regulate the angiogenic response in experimental limb ischemia in mice without toxicity. Looking forward, we hypothesize the existence of driver ncRNAs and their targets in early and advanced phases of disease and seek to uncover their expression, function, mechanism, and interactomes. Using a robust ncRNA platform established in the lab, we will bring together cross-disciplinary expertise to address focused questions that explore new molecular and cellular targets and abnormal endothelial cell (EC)-cell interactions that underlie defects in microvascular perfusion and function in CLTI. For this program, promising new leads have been discovered related to targets involved in: (1) EC permeability and angiogenesis; and (2) vascular smooth muscle cell-EC crosstalk as critical drivers in the microvascular response to CLTI. Single cell and spatial transcriptomics combined with other -omics-based technologies in specimens from patients with CLTI will illuminate driver cell types and targets underlying impaired microvascular perfusion. Novel bioengineered delivery platforms (e.g. colloidal hydrogels incorporating ncRNAs) will be utilized for sustained delivery of promising targets. The outstanding qualifications of our multi-disciplinary team in the ncRNA field, molecular imaging, vascular biology, nanomedicine, bioinformatics, and CLTI coupled with a strong training program uniquely position us to establish an unprecedented molecular view of ncRNAs in the development of CLTI that can inform new paradigms of ncRNA-based therapeutics for this and other ischemic disease states.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Epstein-Barr virus (EBV) is spread through the saliva, where it establishes oropharyngeal infection, invades the tonsils and colonizes the B-cell compartment. Orally transmitted EBV is the cause of infectious mononucleosis and of multiple B-cell and epithelial cancers, including Burkitt lymphoma, nasopharyngeal carcinoma and gastric cancer. Though typically maintained in latent status in cancer cells, lytic infection is increasingly implicated in tumorigenesis of EBV+ B and epithelial cells, including through evasion of immune and anti-apoptotic pathways, and by modulating cytokine and chemokine signaling. Consequently, there is increasing interest in defining factors that regulate EBV lytic gene expression, and an unmet need for antiviral agents that block not only late lytic gene expression as presently available, but also immediate early and early gene expression. Key preliminary data includes human genome-wide CRISPR screens to characterize host cell factors important for EBV lytic reactivation and replication, which highlighted unexpected roles for nicotinamide adenine dinucleotide (NAD+) metabolism in support of the EBV lytic cycle. While NAD metabolism was recently found to be essential for EBV-driven B-cell immortalization, its roles in the EBV lytic cycle remain unstudied. The proposal tests the central hypothesis that EBV subverts the salvage NAD+ nucleotide metabolism pathway to support each phase of the viral lytic cycle. Aim 1 characterizes obligatory NAD+ salvage pathway roles in support of the EBV immediate early lytic phase. Aim 2 characterizes obligatory NAD+ salvage pathway roles in support of the EBV early lytic phase. Aim 3 characterizes EBV lytic cycle remodeling of NAD-capped RNA abundances to evade host innate immunity. Collectively, these studies investigate a novel area of cross-talk between host cell nucleotide metabolism and the viral lytic cycle. They promise to lay a foundation for novel therapeutic approaches that potently block EBV lytic gene expression in epithelial and B-cell contexts. The career development plan will prepare the applicant for transition to independence as an investigator with a multi-disciplinary approach to study metabolomic and epigenetic control of EBV/host interactions.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Lupus nephritis is a chronic, life-threatening autoimmune glomerulonephritis that disproportionately impacts young people with devastating consequences. Despite current standard treatment with glucocorticoids, immunosuppressives, antimalarials, and renin-angiotensin-aldosterone system blockade, lupus nephritis carries a 10-30% risk of end-stage kidney disease as well as increased risks of cardiovascular disease and premature morality. Proteinuria, a key feature of lupus nephritis, is a major risk factor for progressive glomerular filtration rate (GFR) decline and end-stage kidney disease. It is increasingly understood that lupus nephritis needs to be rapidly and aggressively treated with multiple agents during an early window of opportunity, before irreversible kidney damage has occurred. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are now proven to reduce chronic kidney disease progression among patients with diabetic and non-diabetic kidney disease via hemodynamic and metabolic mechanisms that reduce proteinuria, lower blood pressure, and improve metabolic syndrome. Observational studies indicate a possible role for SGLT2i to improve kidney and cardiovascular outcomes for patients with lupus. However, patients with lupus nephritis were largely excluded from randomized controlled trials (RCT) of SGLT2i and are excluded from the current FDA indications. Thus, it is unknown whether SGLT2i use will be safe, tolerated, and effective in immunosuppressed patients with early and active lupus nephritis, who are often subjected to complex medication regimens, but this is a key target population in the early window for the prevention of ongoing and irreversible kidney damage. A large, multicenter RCT trial is needed to determine the safety and efficacy of SGLT2i in patients with active lupus nephritis. To enable the planning, design, and success of this future trial, we propose a two-site, three-year pilot and feasibility trial of dapagliflozin as add-on therapy to standard-of-care for 30 patients with biopsy-proven Class III, IV and/or V lupus nephritis. This will be a concealed allocation, blinded RCT with 2:1 allocation ratio of dapagliflozin 10 mg or matched placebo for 12 weeks. The eligible population will include patients with active lupus nephritis with ongoing proteinuria on standard immunosuppression regimens. We will assess the feasibility of recruiting patients with active lupus nephritis, and pilot test study procedures to incorporate patient preferences for study visit formats, including virtual visits (Aim 1). We will pilot test data collection methods for proposed future trial outcomes, including changes in proteinuria and eGFR, SLE disease activity indices, and patient reported outcomes, and we will estimate changes in proteinuria over 12 weeks with dapagliflozin or placebo (Aim 2). We will detect safety signals, especially genitourinary infections, other infections, and hypovolemia, as well as drug tolerability and adherence to the study intervention (Aim 3). This pilot and feasibility trial will provide critical early insights into the use of SGLT2i for patients with active lupus nephritis and will guide the planning of a larger, definitive multicenter RCT to determine the safety and efficacy of SGLT2i in treatment of active lupus nephritis.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT The mucus layer of the digestive system plays a key role in innate immunity, protecting intestinal epithelium from commensal bacteria, pathogens, and toxins. Goblet cells (GCs), secretory cells residing in the intestinal epithelium, are essential for mucin secretion to form this protective mucus layer and maintain its integrity. Ulcerative colitis (UC) is strongly correlated with a compromised colonic mucus layer and a decrease in the number and function of GCs, eventually resulting in inflammatory flare-ups. Unfortunately, current UC treatments display only limited eƯicacy and high recurrence rates, and mostly target the inflammatory process, without inducing mucosal regeneration. In this proposal, we aim to leverage the powerful regenerative potential of the patient’s own cells by activating colon-resident intestinal stem cells (ISCs) to diƯerentiate into GCs. We hypothesize this will augment mucus secretion and rebuild the broken mucosal barrier, eventually preventing pathogen invasion and the consequent inflammatory cascade. Accordingly, the first aim of our study will include artificial intelligence (AI)-guided identification of small molecules that boost GC diƯerentiation. We plan to build on our expertise in ISC diƯerentiation, combined with leveraging existing large biological datasets, including multi-omics datasets and chemical libraries to identify compounds that stimulate GC diƯerentiation. Our second aim is evaluation of AI-identified compounds in UC murine colon organoids (colonoids), and in colonoids derived from UC patients’ biopsies for identification of the most potent GC inducers in this clinically relevant in-vitro model. Our third aim will be dedicated to assessing the therapeutic impact of the top GC boosting molecules in an acute UC murine model. Our proposed strategy to harness the innate stemness of colonic ISCs is envisioned to result in renewal of the colonic GC pool, enhancement of GC-induced mucus secretion and restoration of the mucus barrier function and its key role in innate immunity. We believe the potent stem-cell boosting molecules identified in this study may eventually be developed into a novel treatment modality to replenish the mucus layer and significantly ameliorate inflammatory flares and related symptoms in UC patients.

NIH Research Projects · FY 2026 · 2026-02

1 There is a significant unmet need to identify disease ameliorating therapies for the treatment of ALS. It is 2 increasingly recognized that neuroinflammation plays a central role in driving the ALS progression. Regulatory 3 T cells (Tregs) are a lineage of CD4 T cells that regulate homeostasis by inhibiting inflammation and dampening 4 innate and adaptive immune cell activation. Human blood-derived Tregs can subdivided into two basic, 5 functionally distinct subsets: memory Tregs (mTregs) which have low proliferative capacity but induce strong 6 immediate ex vivo suppression; and resting/naive Tregs (nvTregs) which are highly proliferative, but weakly 7 suppressive without an ex vivo activation step, and represent the pool from which mTregs are theoretically 8 derived. Tregs have been found to be at lower frequency in ALS patients and exhibit reduced function in ALS 9 patients with faster rates of disease progression. In a proof of concept clinical trial, three patients received a Treg 10 adoptive cell therapy that could slow disease for a short period of time after each Treg ACT administration, 11 although the potential benefit was short-lived, suggesting these Tregs were inactivated by the disease 12 environment. Our proposal aims to identify why Tregs are functionally deficient in ALS and what events cause 13 their low frequency. Our studies using high parameter analyses and methods to test the activity of very low 14 numbers of cells, indicate that ALS-mTregs and nvTregs have distinct mechanisms of dysfunction. Thus, the 15 ALS-mTregs show both low frequency and poor stability in early disease, which would reduce their capacity to 16 function in vivo, while the nvTregs show enhanced loss of function and increased decreased viability that worsen 17 with disease progression. Our goal is to identify the molecules or cells that induce these mechanisms of ALS 18 patient Treg inactivation, as ultimately these mechanisms could be therapeutically inactivated to restore ALS 19 patient Treg function and induce slowing of the disease. Our approach to this goal is described in three aims: 20 AIM 1. ELUCIDATE THE MECHANISMS OF mTREG DYSFUNCTION IN ALS. Our data indicates that 21 ALS-mTregs have reduced frequency in early stages of the disease, and are less proliferative and more prone 22 to lose FoxP3 expression (stability) in vitro. In this aim we will identify the cells and molecules that function in 23 early disease to inhibit mTreg growth and/or lineage stability. 24 AIM 2. DETERMINE THE MECHANISM OF nvTREG DYSFUNCTION IN ALS DISEASE 25 PROGRESSION. ALS nvTregs show increasingly poor suppressive activity as the disease progresses. They 26 also exhibit reduced viability, increased TNFa expression, and a unique gene profile in advanced disease. Here 27 we will explore ALS-nvTreg gene expression and how other cell lineages target and inactivate ALS-nvTregs. 28 AIM 3. EXAMINE HOW LOW-DOSE IL-2 AFFECTS Treg FUNCTION IN ALS PATIENTS. We will use 29 our human Treg expertise to determine if low-dose IL-2 augments Treg function in ALS patients that are being 30 treated under an EAP by our collaborators at the Mass General and the Sean Healey and AMG Center for ALS.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Immune responses to cancer and chronic infection often collapse, corresponding to progression of disease. This collapse is not inevitable, however, and both natural and therapeutic exceptions have been shown occur through re-invigoration of a stem-like progenitor population of T cells. It remains unknown how aberrant type 2 responses are maintained in the face of chronic antigen exposure, rather than succumbing to immune exhaustion or tolerance. In a large scale informatic survey of human type 2 inflammation, we recently identified a stinkingly abundant progenitor-like Th2 population in human disease tissue, the Th2 multipotent progenitor (Th2-MPP). We propose that this aberrant tissue progenitor acts as the mirror image of the exhausted T cells seen in cancer and chronic infection, in this case causing pathology through overactivity of the T cell progenitor system. This project sets out to define the factors that sustain the Th2 progenitor population using human disease tissue and a novel mouse model. The experiments in this proposal are designed to reveal the core features of tissue human and mouse Th2 progenitors and to identify the factors that promote their maintenance. In Aim 1, we will deconstruct the Th2 compartment by comparing aspirin-exacerbated respiratory disease (AERD) and chronic rhinosinusitis with nasal polyposis (CRSwNP), two diseases that are clinically similar, yet thought to be driven by different factors. Using single-cell RNA-seq with T cell receptor-seq, multiomics, spatial in situ transcriptomics, single-cell metabolism assessment, and high-dimensional flow cytometry, we will identify the core and distinct features of the human Th2 compartment including the Th2-MPP population. In Aim 2, we will utilize a newly-developed chronic, multi-allergen mouse asthma model that recapitulates key features of human tissue type 2 inflammation, including a tissue Th2-MPP population that is sufficient to cause airways hyperactivity on adoptive transfer. We will utilize this new model to transcriptomically define the mouse Th2 progenitor in fine resolution and test the disease-causing capacity of this population in vivo. In Aim 3, we will use both a human in vitro system and our new mouse model to test the impact of ongoing T cell receptor signaling, TSLP, IL-33, and glucocorticoid on the Th2 progenitor population. Through these aims, our proposal will use human and mouse systems and cutting-edge approaches to define in detail a previously unrecognized human Th2 progenitor population present across type 2 disease tissues, with the potential to sustain multiple key Th2 lineages. These studies will lay the groundwork for targeting this progenitor system, with the goal of disease modification.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Dolutegravir is widely used for HIV treatment globally, yet glaringly little data on integrase resistance after dolutegravir failure among children are available. While dolutegravir is associated with improved efficacy and decreased resistance compared to other antiretroviral therapy (ART) regimens, a recent study from Malawi found that integrase resistance was present in 30% of select adults failing dolutegravir. While this may be an overestimate, children have multiple risk factors that increase the risk of developing integrase resistance including greater reuse and resistance to companion antiretroviral drugs, lower rates of viral suppression, higher viral load at failure, and more severe immunocompromise. To address this knowledge gap we will quantify integrase resistance in a population of children failing dolutegravir in Nigeria and utilize this resistance data to develop and validate a rapid diagnostic in collaboration with colleagues there. The 2021 World Health Organization HIV Drug Resistance Report specifically calls for surveys of integrase resistance in order to provide early signals of emerging dolutegravir resistance. Our population of highly treatment-experienced children who were rapidly transitioned to dolutegravir ART, of which 12% have detectable viremia, represents such a clinical population at increased risk of developing integrase resistance, and will inform nationally representative surveys of drug resistance. Nigeria is home to more children living with HIV than any other country in the world. A national survey of pre- treatment drug resistance among ART-naïve infants ≤18 months of age (2016) shows high rates of resistance, including to the most widely used companion drugs among children: abacavir and lamivudine. Such resistance may predispose children to develop integrase resistance. Since 2004, APIN Public Health Initiatives has provided HIV care and treatment to over 22,000 children in Nigeria, and thus is uniquely positioned to provide critical drug resistance data from multiple pediatric sites/regions across Nigeria. We propose to evaluate integrase resistance among 500 children in Nigeria failing dolutegravir-ART at two different time points to provide critical data on the evolution of integrase resistance. We will further utilize these data to develop rapid diagnostics to detect specific integrase resistance mutations with the goal of making dolutegravir resistance testing accessible globally via rapid, low-cost assays. These studies address a critical gap in knowledge regarding integrase resistance among children failing dolutegravir ART, will inform future surveys of drug resistance, and will support the development and validation of a rapid integrase resistance assay in this setting. This has the potential to impact international guidance on dolutegravir use and resistance testing for this vulnerable population of children.

NIH Research Projects · FY 2025 · 2025-09

Abstract The accelerated aging seen in space provides a unique opportunity to model diseases, identify therapeutic targets, and test treatments more quickly than on Earth. Space conditions mimic age-related dysfunctions, allowing for faster progression and evaluation of therapies for a number of conditions. Here, we accordingly propose to use extracellular matrix-based scaffolds with interconnected spherical sacs, and human induced pluripotent stem cell-derived cells to develop an immunocompetent, vascularized, and ventilated three-dimensional (3D) model of the human alveolar lung as a truly biomimetic platform for understanding the interplays between pulmonary aging and aging-related disease conditions such as fibrosis, taking the advantage of the microgravity environment at the International Space Station-US National Laboratory. Our central hypothesis is that the use of biomimetic hydrogel matrices with interconnected spherical sacs with suitable stiffness, 3D co-culture of epithelial, endothelial, immune, and fibroblastic cells, in combination with a mechanically active microfluidic bioreactor, will enable simulating in vivo-like conditions under which different cell types would maintain their correct phenotypes and functions. Such a 3D alveolar lung model will for the first time enable faithful modeling of the healthy and fibrotic distal lung combined with microgravity in a human-based and (patho)physiologically relevant platform, providing a powerful tool for disease-modeling and testing new or existing therapeutics and as such envisaged to have significant and urgent implications in space medicine and more importantly, in benefiting life on Earth, and into the future for extended studies on lung diseases.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Radiation exposure causes acute and chronic injuries to cells, tissues, and organs that induce inflammatory and immune complications. Among the most serious complications is predisposition to life-threatening opportunistic infections due to hematopoietic and immune system damage. Long term effects referred to as delayed effects of acute radiation exposure (DEARE) can also occur leading to progressive organ system failure and increased risk of developing cancer or other chronic diseases. Our radiation MCM development research program centers on the concept of targeting innate immune pathways to induce protective anti-microbial immunity and restore immune system homeostasis. We discovered that treating mice with CpG-DNA, a Toll-like receptor 9 (TLR9) agonist found in bacteria and mitochondria, can restore anti-microbial immune function in mice exposed to immune-compromising total body irradiation (TBI) radiation doses. CpG-DNA induces trained immunity in mice via a mechanism involving mesenchymal stromal cells (MSC) effects on hematopoietic stem cells (HSC). The immune regenerative activity of CpG-DNA enhances anti-microbial immunity and reduces DEARE. As such, this project will address the next phases of developing CpG-DNA as a MCM strategy for radiation as well as radiation with traumatic injury. Given the complexity of radiation and traumatic injuries, we will use systems biology research methods to explore detailed changes in the hematopoietic and immune system. To implement translational potential, gender and natural immune “dirty” mice will be included in the experimental design of these pre-clinical studies. We hypothesize that CpG-DNA treatment will help regenerate hematopoietic system recovery by acting on bone marrow hematopoietic and progenitor cells to promote early and late recovery responses in people that may be exposed to radiation with or without trauma. Project aims will (1) systematically test, develop, and optimize CpG-DNA MCM treatment approaches for radiation injuries, (2) identify functional effects of CpG-DNA MCM treatments on infection and immune system recovery after radiation with and without trauma, (3) discover molecular and cellular mechanisms involved in the immune regenerating activity of CpG- DNA. We hypothesize that targeting innate pathways will signaling “upstream” networks to regenerate “downstream” injurious complications of radiation exposure by promoting homeostasis and recovery responses. We expect that the findings from this project will support future translation for CpG-DNA for use in immune compromised people exposed to radiation or other insults that suppress normal immune function and homeostasis.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Millions of adults in the US vary their day-to-day sleep timing to accommodate social and work demands. These irregular sleep schedules promote poor and insufficient sleep. Chronic insufficient sleep increases the risk of errors, accidents and developing various health disorders including neurodegenerative disease. The underlying mechanistic pathways by which irregular sleep schedules promote cognitive impairment and neurodegenerative disease remains poorly understood, and the proposed work will address this critical knowledge gap. Our preliminary data indicate that irregular sleep schedules induce circadian misalignment which we hypothesize is caused by irregular patterns of light exposure. Supporting this hypothesis, our pilot data show that implementing sleep- and circadian-informed lighting (SCIL) attenuated circadian misalignment and improved cognitive function, even in the presence of irregular sleep timing. Additionally, our pilot studies show that more sleep disturbance correlated with more oxidative stress (OS) in brain regions that are associated with cognitive function in humans, and consequently more OS in these regions correlated with poorer cognitive performance. Taken together, our results suggest that circadian misalignment and OS associated with insufficient sleep may be in the causal pathway for cognitive impairment due to irregular sleep schedules and SCIL may be a potential countermeasure. Therefore, the objective of this project is to determine the impact of chronic variable sleep deficiency (CVSD), as a model of irregular sleep schedules, on circadian misalignment, OS and cognition. Additionally, we will explore the role of ambient light exposure and the impact of SCIL conditions in a CVSD paradigm (2 cycles of two consecutive nights of 3 h of sleep followed by one 8-h recovery sleep) on neurophysiologic and neurocognitive outcomes. In a 7-night inpatient study, young healthy adults will be randomized to one of four conditions: dim-light control (8 h sleep each night), dim-light CVSD, room-light CVSD, and SCIL CVSD. The primary outcomes include circadian phase resetting, OS via central glutathione measured by magnetic resonance spectroscopy, and cognitive performance. The aims of the study are to: (1) Determine the causal role of light exposure in circadian phase resetting in CVSD, (2) evaluate the impact of SCIL in CVSD on circadian phase resetting, sleep and cognition, (3) evaluate the impact of sleep deficiency and circadian phase resetting in CVSD on OS, and (4) evaluate the association between cognition and central OS in CVSD. Our work will be a comprehensive evaluation of two mechanistic pathways – circadian misalignment and OS – that can contribute to cognitive impairment associated with irregular sleep schedules. We expect our experimental and analytic paradigm to be a foundational resource that can be extended to future studies examining mechanisms of cognitive impairment and neurodegenerative diseases associated with sleep loss and irregular sleep schedules, and have a positive public health impact by guiding therapeutic strategies for patients with sleep disorders and the general population at large who experience chronic variable sleep deficiency.

NIH Research Projects · FY 2025 · 2025-09

Summary Tuberculosis (TB) remains a significant global health challenge, with the World Health Organization (WHO) estimating 10.8 million new cases and 1.3 million deaths in 2022. Despite advances in TB treatment, the disease continuum includes TB infection, several subclinical stages, and active TB disease, with early TB stages often going unrecognized. Individuals in these early stages can still transmit TB, even without the classic symptoms, complicating control efforts. Traditional TB control strategies focus on diagnosing and treating active TB disease to reduce transmission. However, growing evidence shows that individuals can spread TB before developing recognizable symptoms of active TB disease. This underscores the need for strategies to identify and intervene during the early stages of TB. Chest radiography (CXR) is a standard tool for diagnosing active TB disease, and recent studies suggest it could also detect early stages of TB, particularly in young individuals who often present CXR abnormalities atypical of active TB disease. This proposal aims to investigate the use of CXR to identify young individuals with early stages of TB within a community-based active case-finding (ACF) program in Lima, Peru. We will use existing data from an ACF program initiated in 2019, where 19,950 young individuals were screened for active TB disease but were ruled out from having it. We will use data from the Peruvian National TB surveillance system to identify individuals who developed active TB disease within a year after completion of the ACF program. In Aim 1a, we will evaluate whether among these young individuals, CXR abnormalities were associated with later incident TB. In Aim 1b, we will conduct a nested case-control study based on the cohort of Aim 1a to identify specific CXR abnormal features associated with subsequent incident active TB disease. Artificial intelligence-based computer-aided detection (AI-CAD) of CXRs has expedited the diagnosis of active TB disease, but its focus on typical TB abnormalities may miss individuals at early stages of TB, who usually have atypical abnormalities. Therefore, in Aim 2, we will develop an AI-based CXR reading algorithm tailored for detecting individuals at early TB stages, differing from those designed for active TB diagnosis. This algorithm will be trained on CXR images from individuals in Aim 1b. This study could provide robust evidence supporting CXR as a standard tool for detecting individuals at early stages of TB, enabling timely non-therapeutic or therapeutic interventions to help interrupt further transmission of TB.

NIH Research Projects · FY 2025 · 2025-09

The American Heart Association recently added “Get Healthy Sleep” to “Life’s Essential Eight” health behaviors. Key aspects of healthy sleep – and its converse, sleep health disparities (SHD), however, remain unknown. SHDs are persistent differences in one or more dimensions of sleep health (e.g., sleep deficiency) and circadian misalignment – each of which increases the risk of multiple cardiovascular and other diseases/disorders that disproportionately impact populations (i.e., health disparity populations [HDPs]). SHDs are likely partially driven by environmental and social factors, some of which are determined by geographic location. It is not known (i) how demographic factors impact the probability of SHD and (ii) how neighborhood-level/place-based factors (e.g. noise, longitudinal position within a time zone (as a measure of environmental circadian misalignment [ECM])) affect the probability of SHDs. This lack of information hampers planning of targeted interventions to improve sleep health and therefore other outcomes. Two NIH Institutes convened a 2020 workshop (led by co-Mentor Dr. Jackson) that identified a need to investigate the causes of SHDs and their health and social consequences. A related gap in the 2021 NIH Sleep Research Plan is what geographic factors contribute to SHDs. The proposed specific aims test hypotheses that address this need/gap: 1) estimates of sleep health (e.g., duration, quality, restorative sleep, and timing), and ECM are 1a) worse among HDPs and 1b) vary geographically in the United States, 2) both individual-level and place-based factors (e.g. noise) are associated with SHDs, and 3) Test whether place-based factors mediate sleep health disparities. These aims will be accomplished by linking data from a nationwide public health surveillance project to neighborhood-level factors using Geographic Information Science (GIS) and testing the association between individual-level and neighborhood-level factors and SHDs, and a mediation analysis between the same. The dataset includes validated surveys for sleep and circadian characteristics, detailed demographics, health-related quality of life, and precise respondent location. I am a skilled epidemiologist who requires additional training to conduct this project and become an independent investigator in the field of sleep medicine leading transdisciplinary research in sleep epidemiology with a focus on health disparities. The specific training includes 1) health disparities research, 2) GIS techniques and 3) clinical consequences of poor sleep health and circadian misalignment. I worked with the team of national experts assembled for this training to develop a comprehensive research and training program that builds on my current expertise and will provide the necessary skills for this project and my career. Upon completion, I will be uniquely qualified to study the causes and consequences of SHDs through prospective epidemiologic studies that include objective exposure assessments (leveraging GIS techniques) and robust incident outcome ascertainment.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT As the aging population continues to grow worldwide, age-related chronic heart and lung diseases have become an increasingly serious public health issue. Consequently, understanding the relationships between aging and these diseases is crucial for effective prevention and treatment strategies. However, the complexity of the aging process, which involves cellular senescence, inflammatory responses, and oxidative stress, and its differential impact on individuals, makes it difficult to identify the relationship between specific aging processes and the development of various heart and lung diseases. The recent concept of "ageotypes," which clusters individuals into similar molecular profiles throughout the aging process, offers a framework to identify molecular mechanisms of aging and connect this with chronic heart and lung diseases. However, existing studies of ageotypes have been limited by small sample sizes, short follow-up periods, and insufficient omics data, limiting their overall utility. This proposal aims to generate multi-omic ageotypes to understand the molecular mechanisms of aging that lead to chronic heart and lung diseases. The overall objectives of this proposal are to: 1) develop and validate multi-omic ageotypes using metabolomics and epigenetics data in two large cohorts with electronic medical records (EMR) data; 2) identify the molecular drivers that significantly contribute to each ageotype, particularly in relation to heart and lung diseases; 3) elucidate the relationship between ageotypes and chronic heart and lung diseases. Through personalized approaches for different ageotypes, we may not only improve the treatment of chronic heart and lung diseases but also potentially delay or prevent their onset, thereby having a profound impact on public health. Dr. Yulu Chen is a bioinformatician specializing in using multi-omic approaches to study complex disease phenotypes, particularly respiratory diseases and aging. Her overarching career goal is to become an independent researcher with the skills to enhance the biological understanding and clinical management of aging and related heart and lung diseases through integrative omics techniques. Dr. Chen's strong quantitative and methodological background, combined with the support from a diverse and world-class mentoring and advisory team from the Channing Division of Network Medicine at Brigham and Women’s Hospital and Harvard Medical School, has well-prepared her for the proposed research. The proposed career development plan builds on her previous training and outlines five training objectives to enhance her trajectory toward becoming an independent researcher: 1) expand her skills in integrative omics techniques, particularly network-based approaches for integrating multi-omic datasets; 2) enhance her knowledge and application of epigenomic data; 3) gain a deeper understanding of the phenotypes and experimental measurements of heart and lung diseases; 4) broaden her understanding of the biological mechanisms of aging; 5) improve her skills in research design, mentorship, scientific ethics, and research communication.

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.