Massachusetts General Hospital

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT/PROJECT SUMMARY Acute Graft-versus-Host Disease (aGVHD) remains a critical barrier to clinical success after allogeneic hemato- poietic cell transplantation (allo-HCT) in patients with high-risk hematologic malignancies and non-malignant diseases. The current treatment options are limited and rely heavily on non-specific immunosuppression with high-dose glucocorticoids, which is only partially effective while increasing infection risk and potentially abating the protective Graft-versus-Leukemia (GVL) effect. Emerging evidence highlights the gastrointestinal (GI) tract as a pivotal driver of systemic alloimmunity, but the exact biological pathways involved in the interface between the GI tract and the immune system are incompletely understood, which impedes the development of novel targeted anti-aGVHD approaches. This proposal seeks to investigate the mechanisms of GI-driven T cell repro- gramming during aGVHD to identify novel therapeutic targets. We hypothesize that GI-derived T cells mediate systemic aGVHD-induced immunopathology while being dispensable for the GVL effect, which we will test in the three Specific Aims. Aim 1 will examine how GI-driven reprogramming impacts donor T cell pathogenicity. We will use photoconvertible Dendra2 donor mice to trace, profile, and functionally characterize GI-reprogrammed T cells as they traffic to distal organs during multiorgan aGVHD. Aim 2 will evaluate genetic (Itgb7-mutant T cells) and pharmacologic (anti-MadCAM-1 antibodies) strategies to block T cell trafficking to the GI tract, thereby mitigating extra-GI immunopathology in skin/esophageal aGVHD model induced by transplantation of OVA-spe- cific OT-I T cells to B6-K14.OVA recipient mice with keratinocyte-restricted OVA expression. Aim 3 will employ allo-HCT models in which aGVHD and GVL are mediated by distinct T cell subsets to determine whether GI- driven reprogramming affects the cytotoxic function of tumor-specific T cells in vivo. This project will provide foundational insights into tissue-specific immune regulation and inform the development of precision therapies to control aGVHD while preserving GVL. These findings promise broader relevance to T cell-mediated alloim- mune and autoimmune diseases, paving the way for clinical translation.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY The recent approval of the Respiratory Syncytial Virus (RSV) vaccine for administration in pregnancy presents a novel opportunity to define immune responses of the maternal-fetal dyad, and how that response crosses the placenta and mammary tissue. Recent work indicates that timing of maternal RSV vaccination alters placental antibody transfer to the fetus. To maximize infant protection after maternal RSV vaccination, key gaps in knowledge include: 1. The extent to which maternal vaccination elicits direct fetal antigen-agnostic and antigen- specific cellular responses to augment infant protection from RSV and other infections. 2. How gestational age at vaccination alters maternal antibody response, subsequent placental and breastmilk antibody transfer, and persistence of immunity in the infant. The proposed studies will test the central hypothesis that timing of maternal vaccination, antibody Fc-receptor binding properties, glycosylation profiles, neutralizing antibody levels and non-neutralizing antibody functions are all key determinants of placental and breastmilk antibody transfer to the neonate. These antibody features will work in concert with fetal innate and adaptive immune responses to maternal vaccination, driving protection of the infant through 6 months of age. In a cohort of 400 pregnant women and their infants, this study will examine fetal cellular responses to maternal RSV vaccination, both RSV-agnostic and RSV-specific, by evaluating fetal immune cells isolated from placental villi and cord blood (Aim 1). It will comprehensively profile placentally- and breastmilk-transferred antibodies after RSV vaccination in pregnancy, evaluating IgG subclass, Fc-receptor binding, glycosylation profile, and neutralizing capacity of antibodies using in vivo and in vitro assays (Aim 2). It will then evaluate how antibody properties and timing of maternal vaccination impact the durability of antibody-mediated and cellular immunity in infant blood and breastmilk, through 6 months of age (Aim 3). Machine learning approaches will be used to estimate the magnitude and specific features of protective immune responses induced by maternal vaccination, not only for RSV, but also for influenza, Tdap, and COVID-19. These methods will generate a comprehensive model of durable infant protection from maternal vaccination spanning multiple pathogens. Defining these immune principles across the maternal-fetal dyad will generate key biological insights necessary to optimize neonatal and infant protection.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY More than one million children who are HIV-exposed but uninfected (CHEU) are born to pregnant people with HIV (PPHIV) every year. CHEU have a higher risk of adverse early-life outcomes than HIV-unexposed peers, including neurodevelopmental deficits and a >2-fold risk of growth stunting. The pathophysiology of adverse CHEU outcomes is incompletely understood, but mounting evidence suggests that placental abnormalities play a key role. A better understanding of the causes and mechanisms of poor developmental outcomes in CHEU is essential to improve the care of PPHIV and their offspring. Our overarching goal is to determine which 1) clinical, 2) placental histological, and 3) placental stereologic features predict adverse CHEU neurodevelopmental and growth outcomes. Leveraging our ongoing multi-country (Uganda, South Africa) birth cohort (n=1,200) and linked placental biobank, we will perform state-of-the-art 3D placental stereology and build artificial intelligence (AI) classifier models to predict CHEU child health outcomes, employing causal inference and instrumental variable analysis to account for confounding. We will also perform mediation analysis to determine whether placental features mediate the relationship between clinical and laboratory features and child outcomes. Innovation: Distinct advantages of our proposed research include 1) simultaneous collection and comparison of CHEU and HIV/antiretroviral-unexposed placentas and children, 2) use of rich clinical data and complementary methods [3D stereologic imaging and histopathology] to evaluate associations between placental abnormalities and adverse CHEU neurodevelopmental and growth outcomes, and 3) use of causal inference and mediation analysis methods to identify key and modifiable features. Investigators: Our interdisciplinary team with expertise in placental collection and birth cohorts (Bebell, Gray), placental pathology and AI (Goldstein), bioinformatics, AI, and mediation analysis (Dreyfuss, Kawuma), placental ARV effects (Serghides), developmental psychology (Malcolm-Smith), and pediatric neurodevelopment (Donald) is well-poised to complete this work. Approach: We will leverage biobanked placental samples and extend follow-up of enrolled mother-child dyads in Dr. Bebell’s (R01HD11232) and Dr. Gray’s (R01HD102050) birth cohorts; Dr. Serghides’ laboratory infrastructure, Dr. Goldstein’s AI algorithms, and Dr. Dreyfuss’ mediation analysis and causal inference methods to elucidate the effects of HIV and specific ARV exposure on the placenta and child neurodevelopment and growth through age 5 years via these Specific Aims: 1a) Identify clinical and laboratory features that predict neurodevelopmental and growth outcomes in CHEU, 1b) Determine whether placental histologic diagnoses advance neurodevelopmental and growth outcome prediction, and 2) Incorporate placental stereology features into prediction models for neurodevelopmental and growth outcomes. Identifying HIV- and specific ARV-related placental abnormalities and associations with adverse CHEU outcomes has great potential to improve child health by informing ARV selection in pregnancy and early identification and intervention for at-risk children.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Background: Latino adults in the U.S. have higher prevalence of type 2 diabetes (T2D) and mean HbA1c and are nearly twice as likely to report suboptimal adherence to diabetes medications as non-Hispanic White individuals. Low heath literacy (prevalent among ~40% of U.S. Latino adults) is an important modifiable contributor to suboptimal diabetes medication adherence in this population. Audio-based interventions can improve medication adherence and HbA1c among individuals with low health literacy. However, audio-based interventions have lacked scalability (i.e. rely on person-delivered education) and may not provide on-demand information needed to support sustained adherence. Digital diabetes technology can provide on-demand medication information and support medication adherence, but such tools have generally been limited to written content, which can pose additional challenges for people with low health literacy. Preliminary data: In the parent K23 study, the PI (Dr. Seiglie) adapted an English-language, text message platform (REACH) to an adult Latino population with T2D (REACH-Español). REACH delivers personalized, written content that addresses patient-reported barriers to diabetes medication adherence. At enrollment in the REACH-Español pilot RCT, 84% of participants identified a health literacy barrier to diabetes medication adherence as a primary barrier; the barrier “I have trouble reading medication labels” was selected by a majority of participants with baseline HbA1c >9%. Trouble reading medication labels, which could be contributing to poor glycemic control in this population, cannot be solely addressed through language-concordant written information. An audio- based alternative providing on-demand diabetes medication information in Spanish could overcome written information barriers and improve HbA1c. Research: This proposal aims to develop Audible diabetesRx, an audio-based, text message tool that will provide on-demand diabetes medication information tailored for Latino adults with T2D and low health literacy. Aim 1a will develop an Audible diabetesRx prototype by implementing the user-centered sprint methodology with engagement of Latino adults with T2D (n=12) who selected “I have trouble reading medication labels” in the parent K23, as well as expert stakeholders (user design, health IT, and community pharmacists). Aim 1b will conduct beta and usability testing of Audible diabetesRx among Latino adults with T2D and low health literacy (n=18-24). Aim 2 will assess feasibility and acceptability of Audible diabetesRx in a 3-month pre-post study among Latino adults with T2D and low health literacy (n=30). Impact: This R03 proposal has the potential to develop a novel line of research focused on audio-based, digital tools to address health literacy barriers to medication adherence in T2D. The proposal will focus on U.S. Latino adults with T2D, but study findings could have relevance in other chronic conditions and/or English- speaking populations with low health literacy. Findings resulting from this R03 will serve as the basis for a future R01 application to assess efficacy of Audible diabetesRx and will support Dr. Seiglie’s K-to-R transition.

NIH Research Projects · FY 2026 · 2026-02

Post-TB lung disease (PTLD) contributes substantially to the overall morbidity and mortality associated with TB infection. On a histopathological level, fibrosis is a significant feature of PTLD and likely underpins many associated symptoms and clinical findings. Adjunctive therapies that could be used with traditional anti-TB antibiotics to modulate tissue destruction and pathologic remodeling could improve post-treatment lung health, quality of life, and longevity for TB survivors. To date, our insight into the pathological processes driving TB- associated fibrosis is limited, consequently limiting the development of such adjunctive treatments. In the proposed work, we will begin to address that knowledge gap by creating a baseline understanding of the molecules and cells associated with fibrogenesis during TB infection. Our work will make use of unique resources in the Steyn group, including a Human Tissue Biobank of lung specimens that represent a range of TB- associated fibrotic pathologies, and the unique resources of the Barczak laboratory, who are applying a mouse model to study pathogenic mechanisms of TB-associated fibrosis. In Aim 1, we will use our mouse model and a combination of histopathology, immunohistochemistry, and immunofluorescence to identify spatial correlates of fibrogenesis. We will first test our hypothesis that defined macrophage subsets are spatially associated with fibrogenesis (1A). The idiopathic pulmonary fibrosis (IPF) mouse model is the canonical model for fibrogenesis in lung; we will next test whether molecular and cellular factors identified in the IPF model are associated with TB-associated fibrogenesis (1B). Complementing our hypothesis-driven work, we will use spatial transcriptomics to identify novel candidate molecules, cells, and pathways (1C). In Aim 2, we will use the Steyn lab Human Tissue Bank to benchmark findings from the mouse model and identify clinical drivers of TB-associated fibrosis. We will use metadata to identify clinical correlates of four intermediate-stage fibrosis morphologies (2A). We will then test associations between fibrosis and macrophage subsets (2B), additional molecular and cellular factors relevant in the IPF model (2C), and novel cellular and molecular factors identified in Aim 1C (2D). We will explicitly compare results between mouse and human specimens. We will then test associations between clinical factors and cellular and pathway correlates of fibrosis (2E). In Aim 3, we will use µCT and artificial intelligence approaches to develop algorithms that characterize and comprehensively quantify fibrosis in human lung sections and whole mouse lungs to identify candidate microanatomic contributors to fibrogenesis during TB infection. In addition to enabling a full comparison between mouse and human fibrosis, results of Aim 3 will enable the development of new hypotheses around microenvironmental and anatomical cues for fibrogenesis in TB infection. Successfully completing our three aims will create the foundational knowledge and novel tools necessary to ultimately build a mechanistic model for the path to TB-associated fibrosis and for preclinical testing of candidate interventions. We anticipate this work will directly contribute to new strategies for treating TB.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT Bone morphogenetic proteins (BMPs) play critical roles in development and adult tissue homeostasis. Class I (BMP2 and 4) and class II (BMP5-7) BMPs are the dominant players in specifying cell fate, embryonic patterning and organ morphogenesis. We previously showed that liver endothelial cell (LEC)-derived BMP2 and BMP6 also have a key role to regulate systemic homeostasis of the essential nutrient iron by controlling expression of the liver hormone hepcidin. Indeed, iron homeostasis regulation is the major non-redundant function of BMP6 in vivo, and impaired BMP signaling is the main cause of the iron overload disorder hereditary hemochromatosis. BMPs are dimeric proteins that are made as precursors comprised of a non-signaling prodomain and an active ligand released by proteolytic cleavage. Our work and others' have shown that prodomains play critical roles in ligand folding, dimerization, activation, and receptor interactions. Moreover, many ligand functions are carried out by heterodimers (comprised of 2 different ligands) rather than homodimers. Notably, little is known about BMP2 or BMP6 dimerization, proteolytic processing, and prodomain function. Moreover, BMP6 prodomain mutations are linked to altered hepcidin regulation and iron overload in humans, but the mechanisms are uncertain. Here, we will show that 1) LEC-secreted BMP2 and BMP6 must work together to regulate hepcidin and iron homeostasis in vivo; 2) co-expressed BMP2 and BMP6 form heterodimers that signal more strongly vs homodimers; 2) BMP2 and BMP6 proteolytic maturation and/or subcellular trafficking differ from their closest homologues BMP4 and BMP7; 3) BMP2 prodomain is essential to generate active BMP6 homodimers or BMP2/6 heterodimers in Xenopus embryos, whereas cognate prodomains are essential in LECs; and 4) BMP6 prodomain mutations linked to iron overload impair ligand activity and hepcidin induction in vitro. We hypothesize that BMP2/6 heterodimers are a key ligand for hepcidin and iron homeostasis regulation and that prodomains have critical roles in BMP2/6 maturation and function. In this proposal, we aim to use structural modeling, Xenopus embryos, a human LEC-hepatocyte cell culture system, and novel knock-in mice to elucidate how BMP2 and BMP6 prodomains, and the process of proteolytic maturation, contribute to heterodimer and/or homodimer formation and function, and how BMP6 prodomain mutations impact these processes to impair hepcidin regulation and cause iron overload. Our long-term goals are to understand how BMP signaling is regulated to control hepcidin expression and systemic iron homeostasis, how this process is perturbed in iron disorders, and ultimately to develop new treatments for iron disorders. We will also gain fundamental insights into BMP ligand maturation and prodomain function that will have broader impacts for many other fields where BMP signaling is important, including developmental biology.

NIH Research Projects · FY 2026 · 2026-02

Aneurysmal subarachnoid hemorrhage (SAH) carries high mortality in ~40% and poor outcomes in ~20% of all. About 30% of patients who initially survive the rupture develop early brain injury and delayed cerebral ischemia, both major causes of mortality, prolonged hospital stay, and disability. Microvascular dysfunction and vasospasm, inflammation, spreading depolarizations (SD), and seizures all contribute to poor outcomes. There is no established treatment after SAH except nimodipine and enhancing tissue perfusion via induced hypertension. Therefore, aneurysmal SAH management is an urgent unmet need. We here propose to develop non-invasive transcutaneous vagus nerve stimulation (nVNS) as a novel neuromodulatory intervention targeting SAH. Vagus nerve stimulation (VNS), a neuromodulation technique in clinical use for intractable epilepsy and depression, inhibits SDs and has anti-ischemic, anti-inflammatory, anti-hypertensive, and anti-epileptic properties. However, the need for highly invasive surgical implantation of electrodes around the vagus has so far limited its clinical applications. Recently, non-invasive VNS (nVNS) techniques with excellent safety and tolerability profiles have been developed and approved for clinical use. nVNS is a pleiotropic intervention on multiple targets relevant to SAH (Figure 1). We recently showed that nVNS improves outcomes in animals with ruptured aneurysms and SAH. Building upon these proof-of-concept data, our overarching aim in this translational proposal is to build a foundation for nVNS targeting SAH, better understand the mechanisms, and prepare this novel neuromodulatory therapy for clinical trials in SAH. Aim 1: We will test whether nVNS improves SAH outcomes in three complementary animal models of SAH: prechiasmatic blood injection, endovascular puncture, and skull-base elastase injection to induce aneurysms in the circle of Willis that rupture spontaneously. We will establish nVNS dose-response in both sexes, circadian stages, and aging animals on clinically relevant functional and tissue outcomes to define the therapeutic profile of nVNS in SAH. Aim 2: We will test whether nVNS improves biological substrates of SAH outcomes. We will examine optical resting-state functional connectivity, inflammation using myeloperoxidase MRI, blood-brain barrier integrity using dynamic contrast-enhanced MRI, cerebral blood flow autoregulation and cerebrovascular reserve using laser speckle flowmetry, and microcirculatory thrombi and neutrophil extracellular traps using histology. These will confirm target engagement and bolster our confidence in the therapeutic activity optimized in Aim 1. Aim 3: We will test whether nVNS efficacy in SAH is mediated via central or peripheral vagal pathways by ablating the vagus proximal or distal to the cervical nVNS site, lesioning the principal central vagal relay nucleus tractus solitarius, and pharmacologically manipulating the cholinergic anti-inflammatory pathway activated by nVNS. These experiments will identify the vagal projections and their downstream targets relevant to SAH.

NIH Research Projects · FY 2026 · 2026-01

Abstract The Polygenic Risk Methods Development (PRIMED) Consortium was established to harmonize large-scale genomic and phenotypic data and advance methodological innovation to improve polygenic risk scores (PRS). Within the scope of the PRIMED Consortium, the parent award: Functional and Fine-Mapping Approach to Improve Responsible Risk-modeling of Polygenic Risk Scores (FFAIRR-PRS, U01HG011719) aimed to harmonize and aggregate individual-level data across populations, to share analytic workflows and new statistical genetics frameworks, and to validate these approaches for enhanced polygenic score development, generalizability, and clinical translation. To that end, our team has developed new methods with requisite validation advancing new generalizable frameworks for polygenic risk scoring that have already translated to clinical adoption. Based on these new frameworks and consortium-wide learnings, the goal of this administrative supplement is to complete several ongoing high-impact consortium-wide and site-specific activities that will not yet be finalized within the current project period toward maximal impact for PRIMED. Our research team combines strengths in cardiovascular medicine, statistical genetics, and high throughput genetics and genomics. In Aim 1, we will combine existing PRS from the PGS Catalog using the PRSmix method to enhance cross-trait prediction accuracy and stability and will examine the scale of risk estimation and contextualization effects to optimize fairness in trait-specific PRS modeling across contexts. In Aim 2, we will finalize and disseminate new methodological frameworks, including integrative approaches that involve individual-specific trajectories and rare variant modeling. In Aim 3, we will extend benchmarking and integrative risk modeling efforts across key traits to improve clinical translation. Completion of our aims will further advance PRS accuracy and generalizability and enable methodological advances. We will integrate our learnings to both describe the current state of the field but also provide granular guidance regarding clinical translation and communication with patients.

NIH Research Projects · FY 2026 · 2026-01

PROJECT SUMMARY Significance: Providing antiretroviral therapy (ART) to pregnant women with HIV (WHIV) is a landmark global public health achievement, preventing millions of perinatal HIV infections. However, there are now >1 million children exposed to antiretrovirals (ARVs) born annually, a number expected to stabilize or increase over the next decade as WHIV and women exposed to HIV during conception and pregnancy are increasingly taking ARVs as treatment or prophylaxis against HIV (PrEP). To date, the effects and safety of ARVs taken in pregnancy are not fully established and prior research is limited by lack of objective measurement of ARV exposure, and data are lacking on the effects of ARVs on the placenta. Thus, there is a critical gap in knowledge about the impact of ARVs, including PrEP, and association with objective drug levels taken in pregnancy on the placenta and fetus, information needed for optimal ARV design and to advise women on the effects of ARVs taken as treatment or prevention during pregnancy to inform risk-benefit discussions. Innovation: We propose one of the first studies to simultaneously measure ARV levels in dried blood spots from pregnant women and their children’s hair to quantify drug exposure to PrEP and ART in utero and relate ARV levels to placental findings and birth weight. Distinct advantages of our proposed research over prior studies include 1) simultaneous collection and comparison of placentas from WHIV taking ART, HIV-uninfected women taking ARVs as PrEP, and HIV- uninfected women taking no ARVs, and 2) prospective enrollment and observation of pregnant women and children from these three groups to minimize bias, enhance rigor and reproducibility, and relate placental and birth outcomes to in utero exposures. Investigator team: PI Bebell has expertise in HIV epidemiology in pregnancy and placental effects. Co-I Ngonzi has expertise with HIV and pregnancy outcomes in Uganda. Biostatistician Correia has expertise in analyzing data from observational maternal-child outcomes studies in HIV-affected populations and mediation analysis. Approach: We will leverage stored dried blood spot and hair samples from the PI’s ongoing NIH-funded (R01HD112302) PACO cohort in Uganda, clinical and placental histopathology data from enrolled women and their children, established laboratory infrastructure at UCSF’s Hair Analytical Laboratory and AHRI’s pharmacology laboratory to elucidate the independent effects of HIV and ARV exposure on the placenta and birth weight through these Specific Aims: 1) Compare histologic placental abnormalities by ARV levels in neonatal hair and maternal DBS, and 2) Determine the effects of ARV exposure on birth weight and whether placental abnormalities mediate these effects. Determining the impact of ARVs in pregnancy on the placenta and birth weight and the possible mediating role of the placenta has great potential to improve child health through optimizing outcomes and inform choices for women accessing ARVs as treatment and prevention during pregnancy. By leveraging already-collected samples and data from an NIH-funded study, this proposal will inform practical strategies to improve ARV-related outcomes.

NIH Research Projects · FY 2026 · 2025-11

PROJECT SUMMARY Klebsiella pneumoniae has emerged as a critical human pathogen in the United States and globally. In the United States, K. pneumoniae is the third most common cause of hospital-acquired infections and accounts for 20% of deaths attributable to antibiotic-resistant bacteria. In low- and middle-income countries, K. pneumoniae is a leading cause of childhood mortality and neonatal sepsis. Despite the rising importance of this pathogen, there are no U.S. Food and Drug Administration or World Health Organization-approved vaccines for K. pneumoniae. Our project is designed to address three critical knowledge gaps related to the development of Klebsiella vaccines. First, although a quadrivalent O-antigen vaccine for K. pneumoniae has been proposed, there is insufficient evidence to show that the inclusion of only four O-types would provide sufficient protection against the nine structural subtypes of these K. pneumoniae O-antigens. To address this knowledge gap, we will determine whether human infection with each K. pneumoniae O-antigen subtype results in cross-specific antibody responses against other K. pneumoniae subtypes. This research will provide new and detailed information on the specificity of human O-antigen responses to K. pneumoniae and inform the antigenic composition of a K. pneumoniae O-antigen vaccine. Second, our proposed experiments will determine which K. pneumoniae antigens contribute to functional human antibody responses the bacterium. Specifically, we will determine whether antibody responses to both the capsular (K-) and O-antigens the bacteria through interactions with phagocytic cells and complement. This is important because such functional responses are likely to mediate protection against K. pneumoniae infection. Third, we will determine which types of antibodies are associated with protection against intestinal colonization with K. pneumoniae. If we identify antibodies that are correlated with protection against K. pneumoniae, this will represent a groundbreaking finding and aid in the development of vaccines for this important pathogen. In summary, we expect the proposed studies to generate fundamental insights into immunity against this pathogen and aid in the development and assessment of K. pneumoniae vaccines. Our proposed work will provide critical data to inform the antigenic composition of K. pneumoniae vaccines and new proxy measures to assess vaccine efficacy in pre-clinical and early phase vaccine trials. These insights are urgently needed to address the growing global threat of antibiotic-resistant K. pneumoniae.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT The ongoing overdose crisis in the US, primarily driven by fentanyl, calls for innovative secondary overdose prevention strategies to improve engagement with medications for opioid use disorder (MOUD). Research suggests individuals using fentanyl may require faster or less challenging titration and higher maintenance doses due to their greater opioid tolerance, which differs from the needs of patients using prescription opioids or heroin, the populations for whom MOUD was initially developed. However, regulatory and structural challenges in the US hinder the implementation and rigorous evaluation of such MOUD dosing strategies. Building on our decade-long track record of collaboration, we propose an international collaborative effort to evaluate novel MOUD dosing strategies. We will leverage the Vancouver Injection Drug Users Study (VIDUS), one of the largest and longest-running prospective cohort studies of community-recruited people who use drugs in the world. The VIDUS well represents sub-sets of MOUD patients who bear a disproportionate burden of overdose (e.g., those unstably housed). While Canada faces a similar fentanyl-driven overdose crisis, its more relaxed MOUD regulations have allowed prescribers to implement novel dosing strategies. Further, VIDUS’ comprehensive dataset integrates rich longitudinal behavioral data (e.g., drug use patterns, nonfatal overdoses) with urine drug screen results and linked administrative databases (e.g., health insurance records, pharmacy dispensations, hospital/emergency room admissions, and fatal overdoses), overcoming major limitations in the US datasets and enabling rigorous evaluation of novel MOUD dosing strategies. Our proposal falls under Funding option A: Implement and rigorously evaluate strategies, with three specific aims. Aim 1 is to assess the impact of dosing strategies (i.e., rapid methadone titration, low-dose buprenorphine induction, and higher maintenance doses) on treatment retention, using marginal structural models. Aim 2 is to evaluate whether these dosing strategies reduce illicit drug use and the risks of nonfatal and fatal overdoses, using a comparative interrupted time series design. Aim 3 is to identify barriers and facilitators to adoption, feasibility, and scalability of the dosing strategies in the US through a targeted literature review, natural language processing analysis of social media data, and qualitative interviews with MOUD prescribers. It is designed to ensure that the evidence generated from Canadian settings can effectively inform the adaptation of dosing strategies into US healthcare systems. This project is timely, as there is growing recognition in the US that MOUD guidelines may need adaptation to better address challenges posed by the fentanyl crisis. By addressing challenges with MOUD engagement and overdose prevention, this study aligns with the CDC’s priority to implement and evaluate innovative secondary prevention strategies for reducing opioid-related harm. Our interdisciplinary team, including experts in addiction medicine, causal inference, and data science, is uniquely positioned to contribute insights that will shape future MOUD treatment strategies.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract The Open Health Imaging Foundation (OHIF) Viewer and its libraries, including Cornerstone3D, provide a professional-grade, open-source framework for web-based imaging informatics in cancer research and medical imaging applications. With features such as image review, annotation, segmentation, and a user-friendly interface, OHIF empowers researchers and developers to create custom imaging tools, integrate innovative extensions and workflow modes, and transition traditional desktop platforms to modern, cloud-based solutions. Delivered through a zero-footprint web architecture, the platform eliminates the need for local software installations, significantly improving accessibility and usability. These foundational capabilities were developed under prior grants from the NCI Informatics Technology for Cancer Research (ITCR) U24 program, enabling OHIF to become a leader of imaging informatics for cancer research and beyond. Despite these advancements, further work is required to ensure the platform remains robust, interoperable, and sustainable as it continues to grow and serve an expanding user base. Key challenges include improving reliability in the face of rapid feature development, integrating the platform more seamlessly into modern healthcare IT ecosystems, and addressing the maintenance and modernization needs of critical underlying libraries. These improvements are essential to keep pace with evolving research and clinical demands while continuing to foster a thriving community of contributors and users. To address these challenges, this project will focus on enhancing the testing ecosystem for the OHIF Viewer and Cornerstone3D to ensure reliability across devices and workflows, while supporting sustainable community contributions. Additionally, building on top of the Fast Healthcare Interoperability Resources (FHIR) standard, we will enable real-time interoperability between the Viewer and other healthcare systems, such as measurement reporting systems, streamlining collaboration and synchronization of data. Finally, modernization and harmonization of key libraries, including dcmjs and dicom-parser, will improve performance and long-term usability, ensuring the platform’s continued relevance and impact. By addressing these priorities, this project will enhance the sustainability, usability, and impact of the OHIF platform, empowering cancer researchers and the broader biomedical research community with reliable, scalable, and interoperable imaging tools. These advancements will facilitate collaborative research, improve the integration of imaging data with other healthcare systems, and support the NIH’s vision of fostering robust, FAIR-compliant software tools for modern biomedical research.

NIH Research Projects · FY 2025 · 2025-09

Severe obesity, a population of over 30 million adult Americans, increases rates of acute hypoxemic respiratory failure (AHRF) and leads to cardiopulmonary complications and premature death. Unfortunately, AHRF in severe obesity remains insufficiently characterized, and there are no targeted pharmacologic therapies for this population. The K23 award application aims to address critical knowledge gaps for the care of acutely hypoxemic patients with severe obesity and develop methodologic expertise in functional lung imaging and endothelial biology for the candidate. The mentored research has two aims. Aim 1 will define the association between severe obesity and regional lung perfusion in a novel multicenter AHRF cohort containing functional imaging and clinical data. Aim 2 will test the effect of severe obesity on the pulmonary vasoreactivity to inhaled nitric oxide in a prospective cohort of mechanically ventilated patients with AHRF. Contributions from diabetes and sex will be assessed for both aims. The proposal's central hypothesis is that severe obesity impairs regional lung perfusion and vasoreactivity in AHRF. The candidate's long-term goal is to be an independent patient- oriented translational researcher who develops and tests precision diagnostics and therapies for AHRF patients with severe obesity. The research aims directly inform the training goals to 1) develop advanced knowledge of functional lung imaging techniques, 2) gain methodologic expertise in endothelial biology, 3) acquire skills in clinical trials in critical care settings, and 4) obtain certification in obesity medicine. The training plan includes hands-on laboratory experience, selected graduate coursework, planned research manuscripts, weekly seminars, and frequent mentor meetings that build on a solid clinical epidemiology and biostatistics background. The research project, institutional environment, mentorship team, and content advisors are ideally suited to the candidate's career development. This formative work has the potential to result in a significant shift in the focus of care of AHRF patients with severe obesity by targeting vascular derangements as a guide to personalized therapy. The K23 award will support the candidate's transition to lead independent research aimed at 1) integrating perfusion imaging into the care of AHRF patients with severe obesity, 2) investigating the role of nitric oxide signaling dysfunction on AHRF progression in severe obesity, and 3) identifying pathways of perfusion dysregulation as possible targets for novel therapeutic approaches.

NIH Research Projects · FY 2025 · 2025-09

Significance: Air pollution is the leading environmental cause of death globally and the greatest threat to human health. Ambient and household air pollution are responsible for an estimated 7 million deaths and 192 million years of life lost each year, driven primarily by cardiovascular and respiratory disease, and disproportionately affect children and older adults. Substantial global differences in air pollution exposure lead to higher exposures among some populations, so reducing exposure among these populations is crucial to reduce global mortality. Parallel to global efforts focused on improving country-level air quality through multinational collaborations – which will take decades to reduce individual-level air pollution exposure – the WHO established guidelines for reducing personal air pollution exposure focused on individual-level behavioral modifications. However, to what extent the WHO guidelines are applicable to and known by populations living in resource-limited settings, and specifically sub-Saharan Africa, is unknown. Individual-level motivation to modify behavior to avoid pollution exposure are based upon individuals’ awareness about air pollution, their willingness to act, their ability to change, and competing priorities. Innovation: Herein, using the Health Belief Model, we apply a behavioral health-focused approach to characterize local knowledge, attitudes, and perceptions about air pollution and health among highly exposed populations in Uganda, which will inform the design of a contextually appropriate educational strategy to reduce personal air pollution exposure. Investigators: Our interdisciplinary team, with expertise in air pollution-related cardiopulmonary health (Principal Investigator North, an early career investigator fitting the NIH’s “Next Generation Researcher” goals; co-Investigator Dirajlal-Fargo), behavioral science and qualitative methodology (Ashaba, Psaros), air pollution exposure (Onyango), and observational cohort enrollment and retention (Musiime), will conduct the aims of this grant. Approach: We will leverage the research infrastructure of the CAD-Lung (K23HL154863, PI: North) and TIMING (U01AI168630; PI: Dirajlal-Fargo) studies, which are ongoing observational cohort studies in rural and urban Uganda, respectively. CAD-Lung, based in Mbarara, follows adults at least 40 years of age and TIMING, based in Kampala, follows children and adolescents. We will conduct focus group disussions among a subset of participants in the CAD-Lung and TIMING studies to [Aim 1] explore knowledge, attitudes, and perceptions of air pollution and health, and [Aim 2] design and assess preliminary acceptability/feasibility of a multifaceted strategy (termed the AWARE Toolkit) focused on encouraging behavior change to reduce personal exposure to air pollution. Findings from this study will provide the requisite preliminary data to inform the design of our future R01 hybrid implementation-effectiveness RCT to evaluate the impact, implementation, and cost effectiveness of the AWARE Toolkit among highly exposed populations in East Africa.

NIH Research Projects · FY 2025 · 2025-09

Project Summary-Abstract Adolescence is an important developmental period, yet yearly over 700,000 adolescents experience the onset of an Alcohol use disorder (AUD). Alcohol use affects the developing brain, which compromises the achievement of key developmental milestones and leads to injury, illness, dependency, or death. Despite evidence-based treatments for adolescents with AUD, they often quickly return to alcohol use after treatment. One of the key challenges undermining AUD recovery for adolescents is that treatment often occurs in a setting removed from their home and community, where there are strong social risk factors for returning to use substances. Social identity mapping (SIM) is one interactive way to capture social network risk and protective factors among adolescents. The SIM process involves posing a series of questions with participants to produce a visual map of the individual within their social network using paper, markers, and stickers. This experience results in a visual of the network’s potential influences on one’s substance use behavior. SIM is an innovative and interactive tool for data collection that, combined with a set of standardized, reflective questions, could be integrated as a treatment module to generate new insights by the adolescent. This study will build upon our foundational work in this area which adapted the SIM approach as a data collection tool for adolescents, to finalize a standardized adjunctive intervention module, Social Identity Mapping for Adolescents in Recovery (SIM-AiR), for use with adolescents in clinical settings and conduct an initial pilot. In Aim 1, we will present the SIM-AiR developed during our pilot work with 15 adolescent-focused addiction clinicians to gain their feedback. This feedback will be used to finalize the SIM-AiR adjunctive intervention module in an iterative process through several rounds of feedback and adaptation. In Aim 2, our team will pilot the SIM-AiR intervention module with 60 adolescents (12-19 years old) with AUD. As part of our approach, we will collect patient acceptability feedback and clinician acceptability and feasibility feedback. The pilot will recruit adolescents receiving outpatient AUD treatment to receive the SIM-AiR module and to participate in follow-up study visit to collect acceptability information. SIM-AiR sessions will be coded for fidelity using a checklist developed through Aim 1. Between 3-5 clinicians implementing the SIM-AiR will be surveyed and interviewed regarding their experience using it clinically. This proposal addresses the priority special emphasis group, adolescents, using innovative methods, in response to NIAAA’s PAR-23-249 Alcohol Treatment, Pharmacotherapy, and Recovery Research. Ultimately, our investigative team seeks to contribute to the NIAAA strategic priority of using a life course approach in alcohol research by developing and piloting a novel, yet promising intervention to meet the unique developmental needs of adolescents, which future larger clinical trials can examine and test.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Emerging adults (EAs; ages 18-29 years) have the highest rates of heavy drinking and lowest levels of treatment engagement of any age group. The public health burden of EA alcohol use is immense, costing the U.S. economy billions of dollars each year. Screening and brief interventions (SBIs) are effective at reducing alcohol consumption and problems among EAs and may help to address the treatment gap, yet widespread implementation remains limited due to resource constraints. There is a critical need for innovative, scalable, and cost-effective strategies to increase SBI utilization among EAs engaged in hazardous or harmful drinking. Digital technologies hold promise for addressing the SBI implementation gap given cost-effectiveness and widespread digital technology use among EAs. While digital alcohol interventions have produced small but significant effects on reducing alcohol use and problems, their limited personalization and lack of adaptability may hinder engagement, and addressing this issue may increase the impact of digital efforts. Generative artificial intelligence, namely large language model (LLM)-based conversational agents (e.g., ChatGPT) have the potential to revolutionize automated digital alcohol interventions by allowing for continuous, personalized, and adaptive engagement that is more consistent with a human interaction. In this R34 proposal, we will develop, validate, and conduct an open trial of a LLM-based conversational agent (CA)-delivered brief intervention designed to reduce alcohol use and problems among EAs to establish preliminary feasibility and acceptability. To develop the augmented LLM, we will use instruction fine-tuning to enhance conversational abilities within the context of brief interventions based on high-fidelity recordings of sessions from prior clinical trials and simulated patient-provider interactions. A retrieval augmented generation system will be developed to ensure the model delivers accurate information. The augmented LLM will be incorporated into a CA interface hosted on a web application. To validate the CA’s capability for delivering brief alcohol interventions, we will enroll patient actors (clinical or counseling psychology PhD students) and assign them clinical vignettes depicting a diverse range of EAs engaged in patterns of drinking associated with alcohol use disorder. Patient actors will engage in two randomly ordered online text-based brief intervention sessions for each vignette (one with the CA and one with a human clinician). Blinded dialogues from sessions will be presented to experts and evaluated for treatment fidelity. To maximize and measure initial feasibility and acceptability of the intervention, we will conduct semi-structured interviews (n=20) and an open trial (n=20) with EAs engaged in hazardous drinking. Our primary hypothesis is that the intervention will be deemed feasible and acceptable. We also hypothesize participants will report significant reductions in alcohol use and problems at 1-month follow-up. The intervention developed in this study, if shown to be efficacious in future studies, could improve and increase utilization of alcohol SBIs among EAs, an objective outlined in NIAAA’s strategic plan.

NIH Research Projects · FY 2025 · 2025-09

The acquisition and selection of recurrent, somatic mutations in hematopoietic stem cells (HSCs), termed clonal hematopoiesis (CH), has emerged as a significant risk for the development of myeloid neoplasia and mortality. Mutant HSCs can undergo clonal expansion by outcompeting wild-type HSCs and clonal evolution upon the acquisition of additional genetic alterations. Exposure to cytotoxic therapy is a significant risk factor for developing CH, and CH that arises after such exposures is more likely to carry mutations in genes that regulate the DNA damage response (DDR), with TP53 and PPM1D being the most common. PPM1D encodes a serine/threonine phosphatase that suppresses the DDR and p53 activation. Accordingly, PPM1D is mutationally activated in CH whereas loss-of-function mutations occur in TP53. Despite seemingly convergent functions, there are important biological and phenotypic differences between PPM1D- and TP53-mutant CH which suggests that PPM1D and p53 may drive HSC clonal changes through distinct processes. In addition to directly inactivating p53 via dephosphorylation, PPM1D can regulate the DDR upstream of p53 and changes in cell cycle, senescence, and apoptosis downstream of p53. Though PPM1D-mutant CH is more common and expands more rapidly in both aging and cytotoxic therapy-exposed individuals, TP53-mutant CH confers a significantly higher risk of malignancy. Accordingly, PPM1D- and TP53-mutant clonal evolution are associated with different co-mutation and karyotypic features. Using our genetically modified mouse models (GEMMs), we discovered that mutations in PPM1D and TP53 drive HSC expansion in different ways and hypothesize that the distinct phenotypes of PPM1D- and TP53-mutant CH are due to differences in the activation of the DNA damage response and p53-dependent cellular programs in the setting of cytotoxic therapy and accumulation of genetic alterations. To test this hypothesis, advance mechanistic insights, and guide therapeutic efforts we propose two aims. In Aim 1 we will quantify differences in how Ppm1d activation and Trp53 inactivation alter the immunophenotypic composition of the hematopoietic stem and progenitor cell pools (HSPCs) of our GEMMs at baseline and after genotoxic stress. In Aim 2 we will determine the effects of Ppm1d activation and Trp53 inactivation on the HSPC cell states and transcriptional programs under homeostatic conditions and after a DNA damaging insult. Completing these aims will define the distinct ways PPM1D and p53 shape the immunophenotypic and transcriptional landscape of hematopoiesis and highlight the cellular states and transcriptional programs that may underlie clonal changes. In so doing, we seek to improve prognostication and treatment strategies for CH and clonal evolution. .

NIH Research Projects · FY 2025 · 2025-09

Cognitive deficits are the strongest predictor of functional outcome in in schizophrenia (SZ). Even after psychotic symptoms have been controlled with antipsychotic drugs, debilitating cognitive deficits persist. The lack of a mechanistic understanding of cognitive deficits is a major impediment to developing effective treatments to improve cognition. Novel approaches to understanding the mechanisms of cognitive deficits are needed to guide the development and evaluation of interventions that promote recovery. This is the unmet need that this research proposal addresses. Sleep oscillations are causally related to memory consolidation. In SZ, a deficit in sleep spindles correlates with impaired sleep-dependent memory consolidation (SDMC), suggesting it as a potential mechanism. But increasing spindles with drugs has not led to memory improvement. This likely reflects that spindles do not act alone. Memory consolidation also requires the participation of the hippocampus, which replays memories during sharp wave ripples in the sleep that follows learning. The precisely timed dialogue between cortical slow oscillations, thalamocortical spindles, and hippocampal ripples mediates the transfer of memories from temporary representation in the hippocampus to longer term storage in the cortex (i.e., SDMC). Converging evidence from studies of hippocampal structure and function in SZ, from neuropathology to animal models to neuroimaging, all point to deficient replay as a mechanism of impaired SDMC in SZ. Yet, the contribution of hippocampal replay to SDMC deficits in SZ is yet to be examined. This likely reflects that reliable measurement of hippocampal replay depends on invasive recordings. In this 5-year Mentored Research Scientist Development Award the applicant will use data from epilepsy patients undergoing clinically indicated scalp EEG and intracranial hippocampal recordings to develop a machine learning algorithm to detect hippocampal replay noninvasively based on scalp EEG; apply it to archival data to examine, for the first time, whether individuals with SZ have memory replay deficits during sleep; and evaluate closed-loop auditory stimulation during sleep (CLASS) as a potential intervention to augment memory replay and improve SDMC in SZ. If successful, this research will develop memory replay as a novel EEG biomarker of SDMC; demonstrate that it is impaired in SZ, introduce CLASS as a promising, safe, and potentially scalable intervention to improve SDMC in SZ; and generate pilot data for a future R01. To ensure its success, the applicant will engage in advanced courses and individual instruction in (1) the pathophysiology of SZ, cognitive neuroscience, and clinical trials methodology; (2) machine learning to detect memory replay; and (3) hippocampal physiology and intracranial data analysis. The proposed research, training plan, and the mentorship/advisory team will all support the applicant’s transition to independence and long-term goal of leading a laboratory focused on identifying neurophysiological biomarkers of cognitive deficits in neuropsychiatric disorders and neuromodulation-based interventions to treat these.

NIH Research Projects · FY 2025 · 2025-09

Extracellular vesicles (EVs) have emerged as potent analytes in liquid biopsy, presenting diverse molecular cargo that can potentially inform somatic mutations, resistance profiles, and tumor recurrence. However, EVs remain underutilized in clinical assays due to technical challenges. Tumor-derived EVs comprise a small fraction (<5%) of total circulating EVs, and the marker contents in EVs are often very low (e.g., mRNA). Consequently, current EV analyses necessitate large sample volumes (>2 mL plasma) and sophisticated resources. Innovation. We aim to address these limitations by advancing CampEx (CRISPR-accelerated molecular profiling of extracellular vesicles), an integrated platform for EV molecular analyses with exquisite sensitivity and precision. CampEx embodies our new breakthrough in CRISPR-based biosensing: CRISPR- associated (Cas) proteins first recognize their specific mRNA target, an event that triggers RNA replication and signal amplification. This unique mechanism enables CampEx to differentiate between single-nucleotide polymorphisms while achieving a detection limit in the sub-attomolar ranges. Goals. Our recent study validated the CampEx concept in pre-clinical and clinical samples. Building on these promising results, we aim to advance CampEx to a robust, clinically translatable diagnostic platform. We seek two complementary objectives: i) enhancing CampEx's analytical capabilities to enable high-throughput and comprehensive EV analysis and ii) rigorously evaluating EVs' value for precision oncology. Aim 1. We will expand CampEx's analytical targets (>40 markers). The mRNA detection panel will include i) key driver genes and mutations that account for >90% of cancer cases and ii) markers of chemotherapy resistance. Furthermore, we will incorporate protein detection into the CampEx assay flow, capitalizing on EVs' inherent advantage as multi- cargo carriers. We will validate the designed probes, adhering to regulatory (FDA) guidelines to obtain analytical statistics. Aim 2. We will implement a high-throughput, automated CampEx instrument capable of performing 96 parallel measurements. This new system will incorporate our novel "digital modulation" strategy to enhance the robustness of signal detection. Completing this aim will produce a practical system suitable for routine laboratory applications. Aim 3. We will apply CampEx to analyze clinical plasma samples for early tumor detection and treatment monitoring, focusing on two cancer types: ovarian cancer and colorectal cancer. This study will determine CampEx's clinical assay performance, including sensitivity, specificity, and correlation with clinical outcomes. To accomplish our goal, we have assembled an interdisciplinary team (biosensing, EV biology, clinical research, bioinformatics) and clinical resources. Completing this project will establish CampEx as an impactful platform, enabling multi-marker detection in a cohesive single platform. Ultimately, CampEx will expedite preclinical and clinical readouts, thus augmenting EVs' clinical utility in precision cancer care.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Significance: Low-level viremia (LLV) is considered a category of clinical concern by health agencies due to the potential for adverse individual and public health consequences. As such, there is a need to better understand the downstream effects of LLV, particularly for individuals on tenofovir, lamivudine, dolutegravir (TLD), which is now the most common regimen in sub-Saharan Africa, where the global burden of HIV is highest. Innovation: We propose to enroll a comprehensive, longitudinal cohort specifically for the study of people living with HIV experiencing persistent LLV (pLLV) while on TLD in South Africa (Low-V Africa). This proposal also incorporates cutting-edge plasma and proviral sequencing and integration site studies to explore a novel mechanism of clonal expansion of the HIV-1 reservoir as a contributor to outcomes of pLLV. Investigators: Our expert team of clinical epidemiologists (Suzanne McCluskey, Richard Lessells, Mark Siedner), virologists (Jonathan Li, Nokukhanya Msomi), clinical HIV experts (Mahomed Yunus Moosa), and biostatisticians (Musie Ghebremichael) is well-suited to address these important public health questions. We will build upon well-established collaborations and clinical research infrastructure in South Africa to promote an in-depth examination of LLV in the setting of TLD use through completion of the following specific aims: Specific Aims: Aim 1) The Low-V Africa Study will prospectively enroll and follow a cohort of adults with at least two consecutive HIV-1 RNA viral loads between 50-1,000 copies/mL while on TLD. We will then determine longitudinal outcomes at 96 weeks after enrollment. Specifically, we will determine the cumulative incidence of virologic failure, as well as viral suppression and ongoing persistence of LLV (Aim 1a). We will also determine the cumulative incidence of emergent HIV drug resistance and a hyperactive viral reservoir during pLLV (Aim 1b). Aim 2) We will elucidate pharmacologic, viral, and host factor determinants of the progression to virologic failure among participants in the Low-V Africa Cohort. We will evaluate adherence patterns, as determined by tenofovir-diphosphate concentrations from dried blood spots (Aim 2a), HIV drug resistance (Aim 2b), and the HIV reservoir (Aim 2c) as determinants of progression to virologic failure. We will then define the relative contributions of adherence, resistance, and reservoir to virologic failure following pLLV (Aim 2d). Impact: Aligned with NIH HIV research priorities, knowledge gained from this study will improve our understanding of the outcomes of LLV in the dolutegravir era, paving the way for future studies to determine optimal management for this population in sub-Saharan Africa.

NIH Research Projects · FY 2025 · 2025-09

The major challenges for developing primary prevention strategies for childhood asthma are the early identification of modifiable risk factors (e.g., environmental factors, microbiome) and the heterogeneity of asthma. Our group has applied integrated omics approaches to infancy data, and identified endotypes at high risk for asthma. No study has examined the integrated role of residential greenness, airway microbiome (both composition and functional capacity), and host response during infancy in the development of childhood asthma and its phenotypes. Our central hypothesis is that an interrelation between the residential, airway microbiome, and the host will shape earlylife immunity and contribute to the development of asthma and its phenotypes. We will leverage airway samples and comprehensive environmental, clinical, and omics data from three multicenter prospective cohorts. The 30th Multicenter Airway Research Collaboration Finland (MARC-30 Finland) is an ongoing multicenter cohort study of 408 infants with severe bronchiolitis. The MARC-35 (U01 AI087881) is an ongoing multicenter cohort study of 919 infants with severe bronchiolitis. The MARC-43 (UG3/UH3 OD023253) is an ongoing multicenter cohort study of 599 healthy infants. The present R01 project would extend these well-phenotyped cohorts by generating the residential greenness indices (Normalized Difference Vegetation Index and Green Chlorophyll Index), sequencing airway metagenome and then examining their relations to the development of asthma and its phenotypes by age 6-7 years. In Aim 1, we will identify the integrated role of residential greenness and airway metagenome on developing asthma (and its phenotypes) in severe bronchiolitis infants (MARC-30 Finland and MARC-35). In Aim 2, we will identify the integrated role of residential greenness, airway metagenome, and host genome, on developing asthma (and its phenotypes) in severe bronchiolitis infants (MARC-35 only). In Aim 3, to examine the reproducibility and generalizability of findings from Aims 1-2, we will identify the integrated role of residential greenness, airway metagenome, and host genome, on developing asthma (and its phenotypes) in healthy infants (MARC-43 only). The environmental (i.e., residential greenness and air pollution) and metagenome data generated by this R01 project—along with parallel multi-omics (e.g., genome, DNA methylome, transcriptome, metabolome) and immunological data available—offer an unprecedented opportunity to develop data-driven mechanistic models for childhood asthma and highlight preventive strategies based on the modifiable risk factors.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Peripartum cardiomyopathy (PPCM) is a form of heart failure characterized by left ventricular dysfunction that occurs during late pregnancy or shortly after delivery. This condition causes a sudden weakening of the heart muscle, leading to clinical heart failure and significant reductions in both quality and quantity of life. PPCM remains a leading cause of maternal mortality, accounting for nearly a quarter of all deaths in the late postpartum period. Despite its severe impact, the exact cause of PPCM is unknown, and it often arises in women without identifiable clinical risk factors. Additionally, PPCM disproportionately affects women of self-identified Black race and African descent, even after adjusting for ancestry-specific cardiac risk factors and socioeconomic disparities. Recent studies have linked rare ("monogenic") variants associated with dilated cardiomyopathy (DCM), such as truncating mutations in TTN, to PPCM in about 15% of cases. Moreover, polygenic risk scores (PRS), which aggregate common genetic variants associated with DCM, have shown relevance to PPCM in a broader subset of cases. Notably, we recently identified a common African ancestry-specific loss-of-function mutation in CD36 that accounts for a significant portion of DCM risk in AFR populations. However, it remains unclear: (1) How combining monogenic and polygenic factors could enhance prediction and early detection of PPCM; and (2) The extent to which CD36 variation explains the increased PPCM risk observed in AFR individuals. This proposal aims to expand genomic investigation into PPCM by leveraging the national PPCM- Registry (~470 participants, 40% of AFR ancestry) alongside additional recruitment and biobank data. We will combine data from existing biobanks, where genetic data are available but phenotyping of PPCM is required, and from newly recruited PPCM cases, where detailed phenotyping is available, but genetic data generation is needed. This expanded dataset will provide added power for testing a priori hypotheses and discovering novel PPCM associations, facilitating a more comprehensive understanding of genetic risk in PPCM. Our study aims to: (1) Expand the PPCM-Registry and create a larger, consolidated genetic dataset by integrating genetic and phenotypic data across biobanks and recruited cohorts; this will involve generating new genetic data where needed and standardizing phenotypic data across cohorts to support discovery in this rare condition. (2) Evaluate monogenic and polygenic risk factors for left ventricular dysfunction in all PPCM-Registry participants to understand the combined effect of rare and common variants on PPCM risk. (3) Characterize African ancestry-specific risk for PPCM, focusing on the contribution of the CD36 loss-of-function variant to PPCM incidence among AFR participants, with additional analysis of its impact on observed disparities in PPCM risk. Through this comprehensive approach, we aim to advance understanding of the genomic underpinnings of PPCM to enhance prediction, early detection, prevention, and management of this serious cardiovascular condition, while addressing significant disparities in risk.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY ABSTRACT Genome-wide association studies (GWAS) have been remarkably successful at mapping genomic loci for complex human diseases. However, most studies use case-control designs based on disease occurrence at a specific time point, such as diagnosis. overlooking genetic factors that influence the course of disease over time, including initiation, onset, progression, severity, and therapeutic response. Time-to-event (TTE) phenotypes capture both the occurrence and timing of disease activity. GWAS of TTE phenotypes can identify genetic variants associated with disease onset and progression, providing insights for early prevention and therapies aimed at halting disease progression. Large biobanks like UK Biobank, All of Us, and FinnGen, which combine longitudinal electronic health records (EHR) with genomic data, offer unprecedented opportunities to study genetics of TTE phenotypes. However, limitations remain in current computational and statistical tools, especially for rare variants and admixed populations. Additionally, biobank heterogeneity— differences in sampling strategies, follow-up times, and baseline hazards—poses challenges for meta-analysis of GWAS on TTE phenotypes. This project aims to overcome these barriers by developing innovative computational tools and statistical methods for GWAS of TTE phenotypes in large biobanks and cohorts. Aim 1 focuses on creating scalable methods for rare variant association tests on TTE endpoints, accounting for sample relatedness, population substructure, and high censoring. Aim 2 develops novel approaches to include admixed individuals in GWAS of disease onset and progression over time, enhancing inclusivity and reducing disparities in genetic discovery. Aim 3 improves GWAS and meta-analysis methodologies for TTE endpoints by addressing biases like left censoring, sampling bias, and collider bias, enabling robust integration of data across biobanks. The proposed methods will be evaluated through extensive simulation studies and applied to multiple biobanks. Successful completion of this project will provide new critical tools to advance our understanding of the genetic basis of complex diseases, reduce health disparities, and fully harness the potential of biobank resources for uncovering genetic factors influencing disease onset, progression, and treatment response. These tools and results will be made available as open-source software and public datasets to ensure broad accessibility to the research community. Additionally, we will continue to develop, distribute, and support open- source software packages for the proposed methods.

NIH Research Projects · FY 2025 · 2025-09

Project Summary. The complex dynamics of metastatic cancer, which include processes like plasticity, immune evasion, and therapy resistance, pose significant challenges to effective treatment. While emerging single-cell sequencing technologies now aid in understanding the genetic heterogeneity and clonality, as well as the unique genome expression of individual cancer cells within tumor microenvironments, these methods often fail to fully capture the behavior of living cells, such as migration, division, and regulation of volume and mass. The primary technical bottleneck lies in the inability to read DNA barcodes in live cell states and the limited number of unique fluorescence barcode colors available. Addressing these limitations is crucial for enhancing our comprehension of metastatic cancer and improving treatment outcomes. The proposed K25 project aims to develop a single-cell assay for correlating genome, transcriptome, and dynamic behaviors of metastasis cancer cells in an in vivo mice model using laser particles (LPs). These biocompatible particles emit ultrabright narrowband laser emission, creating unique optical barcodes for a massive number of migrating cancer cells, enabling real-time tracking in vivo and compilation of data from different assays. The project comprises three primary aims: 1. Employing LP to create workflows that correlate single cell sequencing with real-time observations of cancer cell mass, volume, and migration using optical microscopy. 2. Creating multiplet LPs, multiple LPs within one body, to ensure the enduring uniqueness of barcodes for long-term, in vivo tracking of cancer cells. 3. Integrating advancements to enable multidimensional single-cell assays within an in vivo metastatic breast cancer model, linking migration and immune cell interaction data from imaging with single-cell DNA and mRNA sequencing results. The project's key innovations involve correlating the genotype and phenotype of migrating cells, integrating cutting-edge LP technology into in vivo cancer studies, and analyzing high-dimensional single-cell data. Aims 1 and 2 operate independently, while Aim 3 is designed to anticipate potential pitfalls and explore alternative approaches. Each aim is supported by preliminary data. The project spans five years, focusing on application to an in vivo model. Expected outcomes include successfully correlating genotype, genome expression profile, and optical phenotypes with single-cell resolution, as well as uncovering novel insights into tumor metastasis and therapeutic responses. Furthermore, the mentoring and training provided by the advisory team empower the principal investigator of this project, with strong backgrounds in nanophotonics and chemistry, not only to contribute significantly to cancer research but also to advance their career toward independent academic positions.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is a leading cause of cancer deaths in the US and is intricately tied to suboptimal diets. Ultra-processed foods (UPFs), which account for nearly 60% of Americans’ daily calories, emerge as an important risk factor for CRC. Proposed mechanisms include the production of pro-inflammatory metabolites, food processing-introduced carcinogens or additives (e.g., acrylamides, artificial sweeteners, or emulsifiers), and the obesogenic effect of UPFs. Growing evidence linked UPF-related metabolites and microbial species to CRC risk, supporting the hypothesis that UPFs promote CRC by inducing changes in the gut microbiome and metabolites. However, direct evidence evaluating this hypothesis remains scarce. Furthermore, there is a lack of evidence on the feasibility and efficacy of interventions addressing high UPF intake among at-risk populations and CRC patients, posing challenges in the development of cost-effective strategies for CRC prevention and control. The objective of this K99/R00 proposal is to identify gut microbial and metabolomic biomarkers of the UPF-CRC relationship and inform clinical interventions targeting UPFs to improve CRC survivorship. To achieve this objective, I will leverage multi-omics data from large prospective cohorts and integrate a medically tailored meal (MTM) intervention into the oncology care of CRC. The K99 research will focus on characterizing a gut microbial and a fecal metabolomic signature of UPFs and estimating their associations with CRC risk by utilizing comprehensive epidemiologic information and gut microbiome and fecal metabolome data from well-established cohorts – Nurses’ Health Study II (NHS II) and the Southern Community Cohort Study (SCCS) with 65% African American participants. The R00 research will evaluate the feasibility and initial efficacy of a single-arm 6-week MTM intervention targeting UPF intake in improving survivorship among 30 patients with stages I-III CRC recruited from hospitals in the Boston area. Individuals who are socioeconomically disadvantaged will be prioritized for enrollment. MTMs are of rapidly increasing interest to healthcare providers, patients, policymakers, funders, and the scientific community, owing to their promise to address specific health needs and diet-related disparities. Study findings will provide critical insights into the etiopathogenesis of UPF-CRC association relevant to diverse populations and inform the integration of medically tailored dietary interventions into oncology care to improve CRC survivorship. This proposal highly aligns with the NIH/NCI’s strategic plan for gut microbiome research and the use of food as medicine to improve cancer care. Under the mentorship of leading experts from Harvard T.H. Chan School of Public Health, Dana-Farber Cancer Institute, Massachusetts General Hospital, and Tufts Food is Medicine Institute, this rigorous training will expand my expertise in new areas, including gut microbiome and bioinformatics, clinical trial research, and MTM intervention strategy for oncology care, which are critical for my transition to being a productive independent investigator studying the diet-CRC relationship and translating epidemiologic evidence into innovative, affordable tactics for CRC prevention and control.