NHLBI - National Heart Lung and Blood Institute Grants

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT Heparin-induced thrombocytopenia (HIT) is a severe, antibody (ab)-mediated prothrombotic syndrome with high morbidity and mortality. The biochemical basis of the distinction between “pathogenic” platelet-activating antibodies and “benign” non-activating HIT antibodies is not well understood. This results in significant diagnostic challenges and in excessive use of non-heparin alternative anticoagulation that have worse bleeding profiles than heparin. Outcomes in HIT are suboptimal despite current therapy with direct thrombin inhibitors: One-third of affected patients develop thrombosis and one in ten patients dies. The proposed studies will explore key unanswered questions in areas of HIT pathophysiology, diagnosis, and treatment. For Aim 1, we hypothesize the existence of multiple functional classes of HIT antibodies: (1) Pathogenic antibodies that recognize PF4-treated platelets with or without reactivity to PF4-heparin complexes, and (2) Benign abs that recognize PF4-heparin but not platelets treated with PF4. We will identify and characterize these antibody classes by chromatography-based isolation from patient samples and will generate novel HIT monoclonal antibodies in each of these functional classes. Generated monoclonal antibodies will be tested for pathogenicity in a HIT mouse model and results will be correlated with their serologic characteristics. Obtaining and processing normal donor platelets is a major challenge that limits the availability of functional “gold standard” testing in HIT. In Aim 2, we will develop a rapid HIT diagnostic test using the patient’s own platelets treated with PF4/heparin. This will facilitate “in-hospital” HIT diagnosis leading to early detection of this condition. Currently used non-heparin alternative anticoagulants do not address the most proximal event in HIT: Activation of platelets by HIT antibodies. Given this, breakthrough thrombosis is frequently seen in patients under treatment and so is unintended bleeding caused by the potent non-heparin anticoagulants used. In Aim 3, we will use platelet-derived and synthetic chondroitin sulfates of various sulfation levels and saccharide lengths to evaluate their ability to inhibit HIT-antibody mediated platelet activation in vitro and to ameliorate thrombocytopenia in a HIT murine model. In Aim 1, we expect to successfully separate and characterize multiple functional classes of HIT antibodies which will suggest new ways to selectively detect only the pathogenic ones. Developing and optimizing a diagnostic method using the patient’s own platelets in Aim 2 will transform platelet-activation based HIT testing by moving it from the reference laboratory environment to the in-hospital setting. Finally, studies described in Aim 3 will introduce a new class of therapeutics in HIT, chondroitin sulfates, that will prevent thrombosis, but unlike current therapies, will not increase the risk of bleeding. In summary, we anticipate that all three aims of this proposal will lead to a significant impact on pathophysiology, diagnosis, and treatment of HIT.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Cardiometabolic diseases (CMDs) disproportionately affect American Indian (AI) populations. Socioeconomic (SE) determinants of health have gained considerable attention as critical risk factors for CMDs, and SE inequity may be a fundamental feature underlying the disparity in CMDs observed in AIs, although this has yet to be investigated. To comprehensively understand the role of the SE environment on CMDs pathogenesis, investigation into the underlying biological mechanisms is needed. Epigenetic mechanisms provide a unique opportunity to identify plausible mechanisms of this relationship, given they facilitate gene-environment-health interactions. The proposed project will combine multi-level socioecological information with epigenomic and inflammatory proteomic data to understand the complex relationship between the SE environment and endogenous responses that may underlie CMDs and CMD-associated phenotypes. This project will leverage rich data collected from the largest longitudinal, prospective cohort of AIs in the U.S., the Strong Heart Family Study (SHFS), an extension of the original Strong Heart Study, which includes AI communities across Arizona, Oklahoma, and North/South Dakota. During the K99 phase, we will build upon the rich data collected in the SHFS by creating personal, family, neighborhood and cumulative measures of SE adversity from participants in the SHFS cohort at SHFS baseline (Visit 4; 2001-2003) and follow-up (Visit 5; 2005-2009); and we will investigate SE determinants of CMDs (Aim 1). In the R00 phase, we will identify DNA methylation alterations and epigenetic aging changes associated with SE adversity (Aim 2), and we will integrate DNA methylomic and inflammatory proteomic data to identify feasible biological signatures that will better explain SE adversity-induced CMD risk (Exploratory Aim). Dr. Dye will have a dedicated training and career development plan that will supplement the proposed research and build his scientific capacity towards his short- and long-term goals. In addition to didactic training, Dr. Dye will have experiential training and guidance by his mentorship and advisory team of leading experts in fields relevant to this study. Dr. Dye will gain fundamental training in indigenous health disparities research and CMD epidemiology (Dr. Ana Navas-Acien, primary mentor); social epidemiology and health equity research (Dr. Rachel Shelton, co-mentor); social determinants of indigenous health disparities (Dr. Mandy Fretts, advisor); and data science approaches to high-dimensional, -omics data (Zhonghua Liu, advisor). This award will prepare Dr. Dye for an independent research career that will bridge immunoepigenetics, molecular and social epidemiology, and indigenous health sciences for his long-term goals to examine epigenetic mechanisms of socioenvironmental determinants of health in indigenous and under-served communities. This project will be useful for preventative medicine (e.g., policy and interventions) in under-served communities, and identifying biological mechanisms will be invaluable for precision medicine (e.g., therapeutics, diagnostics, prognostics).

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT Ground-level ozone (O3) exposure is a significant global health concern of increasing importance. Annually, an estimated 1 million premature deaths are attributable to O3 exposure, costing the global economy billions of dollars (USD). As global O3 concentrations continue to rise, these significant health and economic burdens are expected to increase. O3 exposure is associated with increased morbidity and mortality of pulmonary diseases. Thus, it is imperative to identify mechanisms by which O3 induces adverse pulmonary effects. It is understood that acute O3 inhalation induces pulmonary injury and inflammation mediated in part by the accumulation of airspace iron. However, what remains unclear are the mechanisms by which O3 induces this dysregulation of pulmonary iron homeostasis and the mechanisms by which this iron accumulation mediates pulmonary injury and inflammation. Preliminary data presented in this proposal indicate that O3 increases lung tissue gene expression of nuclear receptor coactivator 4 (Ncoa4), which is known to facilitate the intracellular degradation of the iron sequestering protein, ferritin. Moreover, preliminary results show that O3 reduces airspace ferritin concentrations. Combined, these data strongly suggest that acute O3 inhalation induces pulmonary NCOA4- mediated ferritinophagy, which may contribute to O3-induced increases in airspace iron. Additional preliminary data reveals that O3-induced lung injury, inflammation, and cytotoxicity correspond with increased concentrations of lipid ozonation products. Altered lipid biochemistry and increased iron concentrations are favorable conditions for the induction of ferroptosis, a programmed cell death driven by iron overload and lipid peroxidation. Potential for O3-induced ferroptosis is supported by preliminary data indicating O3 alters lung tissue expression of genes associated with induction and progression of ferroptosis. Both ferritinophagy and ferroptosis have been implicated in multiple pulmonary disease etiologies. However, it is uncertain what role these mechanisms play in O3-induced pulmonary injury and inflammation. This proposal will investigate the hypothesis that NCOA4- mediated ferritinophagy drives O3-induced ferroptosis and subsequent pulmonary inflammation and injury through completion of two aims. These aims will: 1) assess the role of NCOA4 in O3-induced pulmonary ferritinophagy; and 2) Examine the effect of cell-specific ferroptosis on O3-induced pulmonary injury and inflammation. Completion of these aims will elucidate novel pathways in pulmonary diseases exacerbated by O3 exposure, with potential for identifying therapeutic targets. Now more than ever, this research is critical to reducing global health and economic burdens associated with O3. Additionally, completing these aims will support the proposed training program and provide the applicant with the necessary tools to become a successful independent scientist researching environmental lung disease: 1) advanced laboratory techniques; 2) a strong scientific network; 3) leadership experience; 4) scientific writing skills; and 5) ethical and collaborative research expertise.

NHLBI - National Heart Lung and Blood Institute

BioLINCC makes available online data from over 140 clinical studies and biospecimens from 49 study collections (4.0 million vials) linked at a vial level to the data in the Data Repository. This renewal will strengthen and expand the capabilities of BioLINCC into new areas including indexing phenotypic data, storing and sharing digital images and exploring making resources available through a cloud environment. This expansion will improve access to the NHLBI Biorepository and Data Repository, thereby maximizing their scientific value and utilization by the research community. The contractor shall provide a secure environment and the necessary administrative, statistical, programming, data management and informatics to maintain, enhance and expand the BioLINCC program. The government owned resources include clinical study datasets, computer programs, databases, informatics tools and documentation necessary to maintain the program. Additional electronic resources, such as digital images, may be added to the program over the period of the contract.

NHLBI - National Heart Lung and Blood Institute

Phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile to a proliferative phenotype, plays a causal role in many human occlusive vascular diseases. To better understand key biological events occurring in human vascular diseases, we analyzed proteomic data from human atherosclerotic plaques and genomic data associated with human coronary artery disease. This unbiased analysis revealed that many genes involved in vesicle trafficking/fusion are over-represented. Previous studies have shown that the lipid kinase PIK3C3 is an essential regulator of vesicle trafficking/fusion. However, its functional role in VSMCs remains completely unknown. To examine the role of PIK3C3 in VSMCs, we generated inducible SM-specific Pik3c3 knockout (iSM KO) mice driven by Myh11-CreERT2 transgene. Unexpectedly, Pik3c3 iSM KO mice exhibited lethality 4 weeks after deletion of Pik3c3, due to a pseudo-obstructive intestine resulting from deletion of Pik3c3 in visceral SMCs in addition to VSMCs. The iSM Pik3c3 KO mice also exhibit dramatic remodeling of the vascular wall including thickening, aneurysmal dilation and spontaneous neointima. Proteomic analysis and bulk RNA- seq of Pik3c3-deficient aorta revealed loss of contractile proteins while increased expression of inflammation genes and targets of the Hippo-YAP1 pathway which has been shown to be critical for VSMC development and phenotypic modulation. Single cell RNA-seq revealed that Pik3c3-deficient aortic VSMCs almost completely lose their identity of contractile VSMCs while acquiring markers of inflammatory cells and mesenchymal stem cells. These exciting data suggest a previously undocumented role for PIK3C3 in maintaining SMC identity. Mechanistically, Pik3c3 inactivation induced YAP1 protein expression and silencing Yap1 largely restored a contractile phenotype in Pik3c3-deficient VSMCs. We hypothesize that PIK3C3 is a “master” regulator of the contractile phenotype of VSMC via regulating autophagosome-mediated degradation of YAP1. Three specific aims are proposed to test this hypothesis. To circumvent the early lethal visceral phenotype seen with Myh11- CreERT2 transgene, in Aim 1 we will employ a novel vascular-specific inducible Itga8-CreERT2 mouse to generate VSMC-specific Pik3c3 KO mice. Atherosclerosis will be induced using PCSK9 AAV and the effects of VSM- specific deletion of Pik3c3 on lesion formation will be evaluated. Wire injury-induced neointimal formation will be assessed as well by using this novel KO mouse model. Aim 2 will test that YAP1 is a critical mediator conferring the effects of Pik3c3 deficiency on VSMCs. YAP1 will be pharmacologically and genetically inactivated, and its effect on vascular remodeling and gene expression will be determined. Aim 3 will test that YAP1 protein accumulation induced by Pik3c3 deficiency is due to the impaired autophagic flux that attenuates autolysosome- mediated YAP1 degradation. Proposed studies will determine the role of PIK3C3 in autophagic flux in vivo and the role of ubiquitin and p62/SQSTM1 in PIK3C3-mediated degradation of YAP1 in human VSMCs in vitro. Completion of these studies will provide novel insights into the mechanism of controlling VSMC phenotype.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Coronary artery disease (CAD) remains the leading cause of death in the Western world despite significant advances in early detection and extensive use of lipid-lowering and anti-hypertensive drugs. To date, no single drug has been developed to target the primary disease process in the vessel wall. A complete understanding of the disease susceptibility is urgently needed to develop additional therapies. Common forms of atherosclerosis involve environmental factors, hundreds of genetic variations, and their interactions, each of which exert a relatively small effect on disease susceptibility. The most recent genome-wide association study (GWAS) in nearly six hundred fifty thousand individuals identified 175 independent variants associated with increased risk for CAD. However, most of the underlying genes and the related mechanisms of how these variants contribute to the disease process remain unknown. This proposal outlines an integrative genetics study in a unique resource of human aortic smooth muscle cells (SMCs) isolated from 151 genotyped multi- ethnic heart transplant donors to discover the CAD-associated variants that perturb SMC gene expression and their downstream functional consequences. In recent studies, we measured gene expression in quiescent and proliferative culture conditions representing the transdifferentiation of SMCs from a healthy to an atherogenic phenotype. We identified 84 genes whose expression was associated with CAD variants in GWAS loci. However, the causal genetic variants in these loci remain to be elucidated. Therefore, as part of the proposed studies, we will first perform massively parallel reporter assays to identify the variants that modulate gene expression in SMCs. We will also take advantage of the natural variation in gene expression to construct co- expression and Bayesian networks to understand how the predicted candidate causal genes function in SMCs. We will refine these networks by mapping regulatory elements to nascent RNA transcripts in response to pro- inflammatory cytokines. We will then validate our predictions in gain and loss-of-function experiments in cultured SMCs. We will also validate our predictions in well-phenotyped coronary artery specimens from cases of unexpected sudden death by performing immunohistochemical analysis of proteins encoded by genes that are predicted to play a key role in atherosclerosis-relevant SMC phenotypes. The overall goal of the proposed studies is to integrate systems genetics and computational biology leading to mechanistic predictions of the gene networks that are perturbed by CAD. Besides understanding CAD loci, these integrative genetics studies will provide a useful window into the flow of biological information from genetic variants to SMC gene expression and atherosclerosis-relevant phenotypes.

NHLBI - National Heart Lung and Blood Institute

he Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the correlates, predictors, and progression of subclinical cardiovascular disease (CVD) in a diverse population-based sample of men and women aged 45-84 who had no evidence of clinical CVD at baseline. During the initial funding period of MESA, 6,814 participants were recruited from six Field Centers during 2000-2002 and examined for evidence of subclinical coronary atherosclerosis, using computed tomography, cardiac MRI, carotid ultrasound, flow-mediated brachial artery dilation, radial artery tonometry, ankle-brachial index measurement, and retinal photography. A number of other variables including abdominal aortic CT, carotid MRI, cardiac MRI tagging for measures of regional myocardial function; established and putative laboratory risk markers; socioeconomic, psychological, behavioral and environmental characteristics; and genetic variants were assessed in subsets of the MESA cohort. Examinations of selected components were repeated over six subsequent examinations spanning approximately 20 years and the cohort has been continuously followed for clinical CVD events since the baseline examination. This contract aims to continue the follow-up and examination of the MESA participants in an effort to address the following scientific objectives: 1) enhance statistical power to perform analyses of predictors of clinical outcomes, particularly in informative subgroups; 2) study the progression of subclinical to clinical CVD; and 3) identify new risk factors or interactions among factors that inform disease pathophysiology. In addition, the following operational goals will be addressed: 1) continue cohort follow-up and information collection to document clinical events; 2) continue to foster scientific collaborations; and 3) conduct a limited clinical examination of the MESA participants as a platform for ancillary study examination components. The study will continue to support in-depth ancillary studies that are funded outside of the NHLBI contract. These studies will be operationally integrated into the main study, and the data will be shared current MESA and NIH data-sharing policies. The study’s data will be provided to interested investigators through a defined process that encourages maximum data utilization while protecting participant confidentiality.

NHLBI - National Heart Lung and Blood Institute

The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the correlates, predictors, and progression of subclinical cardiovascular disease (CVD) in a diverse population-based sample of men and women aged 45-84 who had no evidence of clinical CVD at baseline. During the initial funding period of MESA, 6,814 participants were recruited from six Field Centers during 2000-2002 and examined for evidence of subclinical coronary atherosclerosis, using computed tomography, cardiac MRI, carotid ultrasound, flow-mediated brachial artery dilation, radial artery tonometry, ankle-brachial index measurement, and retinal photography. A number of other variables including abdominal aortic CT, carotid MRI, cardiac MRI tagging for measures of regional myocardial function; established and putative laboratory risk markers; socioeconomic, psychological, behavioral and environmental characteristics; and genetic variants were assessed in subsets of the MESA cohort. Examinations of selected components were repeated over six subsequent examinations spanning approximately 20 years and the cohort has been continuously followed for clinical CVD events since the baseline examination. This contract aims to continue the follow-up and examination of the MESA participants in an effort to address the following scientific objectives: 1) enhance statistical power to perform analyses of predictors of clinical outcomes, particularly in informative subgroups; 2) study the progression of subclinical to clinical CVD; and 3) identify new risk factors or interactions among factors that inform disease pathophysiology. In addition, the following operational goals will be addressed: 1) continue cohort follow-up and information collection to document clinical events; 2) continue to foster scientific collaborations; and 3) conduct a limited clinical examination of the MESA participants as a platform for ancillary study examination components. The study will continue to support in-depth ancillary studies that are funded outside of the NHLBI contract. These studies will be operationally integrated into the main study, and the data will be shared current MESA and NIH data-sharing policies. The study’s data will be provided to interested investigators through a defined process that encourages maximum data utilization while protecting participant confidentiality.

NHLBI - National Heart Lung and Blood Institute

The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the correlates, predictors, and progression of subclinical cardiovascular disease (CVD) in a diverse population-based sample of men and women aged 45-84 who had no evidence of clinical CVD at baseline. During the initial funding period of MESA, 6,814 participants were recruited from six Field Centers during 2000-2002 and examined for evidence of subclinical coronary atherosclerosis, using computed tomography, cardiac MRI, carotid ultrasound, flow-mediated brachial artery dilation, radial artery tonometry, ankle-brachial index measurement, and retinal photography. A number of other variables including abdominal aortic CT, carotid MRI, cardiac MRI tagging for measures of regional myocardial function; established and putative laboratory risk markers; socioeconomic, psychological, behavioral and environmental characteristics; and genetic variants were assessed in subsets of the MESA cohort. Examinations of selected components were repeated over six subsequent examinations spanning approximately 20 years and the cohort has been continuously followed for clinical CVD events since the baseline examination. This contract aims to continue the follow-up and examination of the MESA participants in an effort to address the following scientific objectives: 1) enhance statistical power to perform analyses of predictors of clinical outcomes, particularly in informative subgroups; 2) study the progression of subclinical to clinical CVD; and 3) identify new risk factors or interactions among factors that inform disease pathophysiology. In addition, the following operational goals will be addressed: 1) continue cohort follow-up and information collection to document clinical events; 2) continue to foster scientific collaborations; and 3) conduct a limited clinical examination of the MESA participants as a platform for ancillary study examination components. The study will continue to support in-depth ancillary studies that are funded outside of the NHLBI contract. These studies will be operationally integrated into the main study, and the data will be shared current MESA and NIH data-sharing policies. The study’s data will be provided to interested investigators through a defined process that encourages maximum data utilization while protecting participant confidentiality.

NHLBI - National Heart Lung and Blood Institute

The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the correlates, predictors, and progression of subclinical cardiovascular disease (CVD) in a diverse population-based sample of men and women aged 45-84 who had no evidence of clinical CVD at baseline. During the initial funding period of MESA, 6,814 participants were recruited from six Field Centers during 2000-2002 and examined for evidence of subclinical coronary atherosclerosis, using computed tomography, cardiac MRI, carotid ultrasound, flow-mediated brachial artery dilation, radial artery tonometry, ankle-brachial index measurement, and retinal photography. A number of other variables including abdominal aortic CT, carotid MRI, cardiac MRI tagging for measures of regional myocardial function; established and putative laboratory risk markers; socioeconomic, psychological, behavioral and environmental characteristics; and genetic variants were assessed in subsets of the MESA cohort. Examinations of selected components were repeated over six subsequent examinations spanning approximately 20 years and the cohort has been continuously followed for clinical CVD events since the baseline examination. This contract aims to continue the follow-up and examination of the MESA participants in an effort to address the following scientific objectives: 1) enhance statistical power to perform analyses of predictors of clinical outcomes, particularly in informative subgroups; 2) study the progression of subclinical to clinical CVD; and 3) identify new risk factors or interactions among factors that inform disease pathophysiology. In addition, the following operational goals will be addressed: 1) continue cohort follow-up and information collection to document clinical events; 2) continue to foster scientific collaborations; and 3) conduct a limited clinical examination of the MESA participants as a platform for ancillary study examination components. The study will continue to support in-depth ancillary studies that are funded outside of the NHLBI contract. These studies will be operationally integrated into the main study, and the data will be shared current MESA and NIH data-sharing policies. The study’s data will be provided to interested investigators through a defined process that encourages maximum data utilization while protecting participant confidentiality.

NHLBI - National Heart Lung and Blood Institute

Abstract Support is requested for a Keystone Symposia conference entitled “Cardiometabolism in Health and Disease,” organized by Drs. Daniel P. Kelly, Rong Tian and William C. Sessa, with scientific programming input from Keystone Symposia. The meeting will take place January 26–29, 2026 at the Keystone Resort in Keystone, Colorado. There has been a groundbreaking surge in knowledge regarding the intertwined health challenges of obesity and cardiovascular disease. Cardiovascular outcomes in recent trials have unveiled an extraordinary, though not fully understood, cardioprotective effect of diabetes and obesity medications. Concurrently, innovative technologies now enable comprehensive real-time analysis of systemic, organ, and cellular metabolism under these treatment regimes. This Keystone Symposia meeting will delve into critical topics in cardiometabolism in both health and disease, including the metabolic foundations of heart and vascular health/disease; the interplay between organs that underpins the synergy among obesity, insulin resistance, and cardiovascular disease; the mechanisms by which new drugs, such as SGLT2 inhibitors and GLP-1 receptor agonists, mitigate cardiovascular events; and the influence of environmental factors, such as diet and circadian rhythms, on cardiovascular health and disease. Conference sessions will highlight presentations from global experts and encourage interactive discussions relevant to the understanding and treatment of the growing unmet health problem of heart and vascular disease in the growing population of patients with obesity and diabetes. Additionally, this conference has been paired with another Keystone Symposia conference, “Obesity Therapeutics: Unlocking Benefits and Minimizing Side Effects,” and will present groundbreaking research from both basic and translational science on the treatment of obesity and cardiometabolic disease. In this regard, this pairing provides greater opportunities for cross-fertilization of ideas and the initiation of novel research directions and collaborations among a multidisciplinary group of leading researchers.

NHLBI - National Heart Lung and Blood Institute

ABSTRACT There is increasing knowledge that volunteering is salutary for volunteers’ cardiovascular health. At the same time, more than 50% of adults over the age of 50 in the U.S. report at least one cardiovascular risk such as hypertension, high cholesterol, obesity, and chronic inflammation. Despite decades of research indicating that frequent volunteers show better cardiovascular disease (CVD) biomarkers, little is known whether frequent and sustained volunteering affects change in CVD biomarkers in multiple population subgroups, net of selection into volunteering. Further, genetic susceptibility to CVD biomarkers has never been studied in the context of volunteering. Our preliminary data show that frequent volunteering (200+ hours a year) predicts favorable CVD biomarkers, including chronic inflammation, systolic, and diastolic blood pressure in longitudinal analysis even when selection effects are considered through inverse probability treatment weighting. This highlights a critical need for understanding the pathways by which genetic, social, and behavioral factors affect cardiovascular health in older adults (NIA strategic research priorities B-2). In response to PA-20-185 and NOT-AG-21-020 Maximizing the Scientific Value of Secondary Analyses of Existing Datasets, the present study uses the Health and Retirement Study and seeks to understand whether changes in volunteering are linked to CVD biomarkers over a decade after adjusting for selection into volunteering and pre-baseline characteristics, and whether these links are stronger for multiple genetic, demographic, and socioeconomic subgroups. Using seven CVD biomarkers and polygenic risk scores, this study addresses three specific aims: Aim 1) examine the longitudinal effects of sustained volunteering on CVD biomarkers (N=18,847), Aim 2) test the associations between genetic predictors of CVD biomarkers, volunteering and CVD biomarkers in multiple ancestry groups (European N=8,400, African N=1,605), and Aim 3) assess the effect heterogeneity of volunteering on CVD biomarkers in multiple genetic, demographic, and socioeconomic subgroups. This project seeks to quantify the effects of volunteering on multiple CVD biomarkers while addressing important questions about selection effects and genetic susceptibility for a better causal inference. Addressing this gap in research is critical for developing new public health policies and biobehavioral and social interventions for heart-healthy older adults.

NHLBI - National Heart Lung and Blood Institute

Abstract Support is requested for a Keystone Symposia conference entitled “Hematopoiesis,” organized by Drs. Vijay G. Sankaran, Anna E. Beaudin and Esther Obeng, with scientific programming input from Keystone Symposia. The meeting will take place February 23–26, 2026 at the Keystone Resort in Keystone, Colorado, USA. Hematopoiesis is a fundamental biological process that underlies the production of all blood and immune cells, and consequently drives immune function, oxygen transport, and tissue homeostasis. Alterations in hematopoiesis can lead to a wide spectrum of disorders and conditions ranging from anemia to immunodeficiencies, inflammatory disorders and blood cancers. Given the vital role of hematopoiesis in health and disease, this conference will explore the molecular and cellular mechanisms that govern blood cell development and maintenance, highlight the latest technological advances in the field and underscore the broader

NHLBI - National Heart Lung and Blood Institute

The overall goal of the Women?s Health Initiative (WHI) Renewal is to continue to serve as a resource for innovative epidemiological research and to expand knowledge about the determinants of cardiovascular disease among older women, successful aging in the absence of cardiovascular disease, and maintaining quality of life in the presence of cardiovascular disease (resilience).

NHLBI - National Heart Lung and Blood Institute

Project Summary The Gordon Research Conference (GRC) titled Biology of Acute Respiratory Infection meets every 2 years and focuses on advancing the frontiers of science through presentation of cutting-edge and unpublished research in the field. The theme for 2026 is Integrated Protection Across the Respiratory Tract. The conference program includes a wide range of speakers and discussion leaders from institutions and organizations worldwide, concentrating on the latest developments in the field. This BARI-GRC focuses on big problems facing the field of acute respiratory infections and the ever-evolving interactions between pathogens and host affecting human biology. The GRC is preceded by the Gordon Research Seminar (GRS), a unique forum for trainees and early career scientists with comparable levels of experience to present and exchange new data and cutting-edge ideas. The goals of the Biology of Acute Respiratory Infections GRC/GRS are to 1) To create a multidisciplinary platform highlighting pathogens across different kingdoms, enabling dissemination and interpretation of the latest scientific discoveries related to acute respiratory infections with a focus on the impact on human biology; 2) To generate a welcoming environment for all that empowers the scientific and career development of early- stage researchers. This conference venue facilitates mentorship and training of junior scientists who will benefit from these multidisciplinary interactions. The format (both formal and informal), size (< 200 attendees), and content of the conference (unpublished, cutting-edge, cross-disciplinary) are designed to maximize opportunities for early-stage investigators to directly interact with leaders in the field, foster collaborations and employment opportunities in a collegial environment. We have developed a program with a unifying theme of One Airway and integrated protection across the entirety of the respiratory tract. We will highlight varied pathogens which can cause acute pneumonia including bacteria (intracellular and extracellular), viruses, parasites and fungi. This meeting provides the single-most comprehensive venue for discussing the latest advances in pneumonia biology.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY The objectives of the 2026 GRC “Lymphatics” are to present state-of-the-art research on the lymphatic vascular system, to fuel scientific exchange across scientific disciplines and expertise, and to spearhead new ideas and collaborations. The meeting will bring together investigators from all backgrounds and from all career stages, converging on lymphatics as one common theme. Specific Aims are (1) To present conceptual advances in research of the lymphatic vascular system and its pathologies; (2) To discuss paradigm shifting findings of lymphatics in different organ systems and their contribution to disease; (3) To integrate knowledge from different disciplines; and (4) To nurture junior investigators and trainees entering the lymphatic research field. Sessions will cover conceptual advances in development and disease of lymphatic vessels from basic aspects to potential clinical applications. The meeting will highlight recent insights into the diversity and organ-specificity of lymphatic endothelium. Novel molecular regulators for lymphatic vasculature during bone development, Schlemm’s canal in the eye and lacteals in the intestine will be discussed. New factors regulating lymphangiogenesis and lymphatic integrity will be introduced. Advances in research on lymphatic malformations, lymphedema and other congenital lymphatic diseases will be discussed. The meeting will also present emerging concepts on the role of lymphatics in atherosclerosis, myocardial infarction, and congestive heart failure. Paradigm shifts in the field will be presented, and crosstalk between lymphatics and immune system discussed. Advances in understanding how lymphatics contribute to disease, including cardiovascular inflammation, cancer, autoimmune and neurodegenerative diseases will be highlighted. A key goal for this meeting is to serve as a platform for growth of lymphatic research, and for helping to promote new scientists entering this research field. Abundant opportunities for the presentation of research by early career investigators will be provided. The GRS on Lymphatics organized by junior investigators will provide opportunities exclusively for junior investigators to present their work and form collaborations. Aside from presentation and poster sessions, a career development session will also be held during GRS to provide guidance to those just getting their start in the lymphatic research field, and to discuss strategies for how to navigate issues impeding lymphatic research or obstacles to participation by incoming lymphatic researchers. A patient session will also be held to allow researchers to hear from those suffering from lymphatic diseases and hear their perspective on the potential promise of translating lymphatic research into new therapies. The sponsoring organization is dedicated to advancing the frontiers of science. In accordance with its mission, this conference will place emphasis on the presentation of unpublished data, high-quality science and rich discussions in many fields, such as cardiovascular disease, cancer, immunology, metabolism and neurobiology. We anticipate that the opportunities provided to young investigators participating in this conference will facilitate their rise as future leaders of the lymphatic research field.

NHLBI - National Heart Lung and Blood Institute

The 2026 Gordon Research Conference (GRC) on Plasminogen Activation and Extracellular Proteolysis and the associated Gordon Graduate Research Seminar (GRS) are paired conferences held sequentially at the same location in Ventura, CA. The GRS will take place on February 7-8, and the GRC on February 8-13, 2026. The GRC has been held continuously every two years since 1990 and enjoys an outstanding international reputation. In this 20th GRC, we will discuss breakthrough findings in plasminogen activation and extracellular proteolysis in areas such as vascular biology, central nervous system function and dysfunction, trauma, tissue homeostasis and regeneration, hematopoiesis, angiogenesis, stem cell biology, metabolism and obesity, tumor biology, cardiovascular function, and aging. For the 2026 GRC meeting, emphasis will be placed on bringing together the biomedical practice with the biology of plasminogen activation and other extracellular proteases, their effectors and associated pathways, as they are relevant to multiple diseases and disorders. Basic and Physician Scientists will discuss the relevant clinical needs and possible therapeutic strategies that can be accommodated using the knowledge generated through basic science. Early and mid-career investigators in the field will have the chance to present and discuss their new and exciting findings alongside senior, established researchers. Basic research, technological advances, and cutting-edge therapeutic approaches in the field of extracellular proteases will be debated and discussed, with the expectation that new collaborations and scientific discoveries will develop from these in-person interactions. Research themes of the 2026 GRC on Plasminogen Activation and Extracellular Proteolysis will capture the most exciting areas of contemporary cutting-edge research in the field. Emerging roles for molecules of the fibrinolytic system and other proteases in pathologic settings such as cancer, cardio- and cerebrovascular disease, metabolic complications, aging, trauma, and neurological diseases will be presented. The development and application of novel technologies in the field will also be discussed. Each session will include a discussion of how basic research in our field can help conquer human disease. The associated GRS will provide a venue for pre- and postdoctoral trainees to discuss their research in a collaborative and stimulating environment to help build their informal network of peers and colleagues. We expect that the 2026 Plasminogen Activation and Extracellular Proteolysis GRC and GRS will bring together a group of highly motivated and interactive participants with different scientific backgrounds to engage in intensive discussions at the frontier of research related to the plasminogen activation system and associated extracellular proteases in an “off-the-record” fashion. The information gained from this meeting will advance the plasminogen activation/extracellular proteolysis field by teaching us about additional direct and nuanced roles for these proteins, which should in turn stimulate the development of new applications and strategies to improve the diagnosis, prevention, and treatment of a wide range of diseases.

NHLBI - National Heart Lung and Blood Institute

The Strong Heart Study (SHS) is a longitudinal observational study of two combined cohorts followed prospectively: the original SHS cohort recruited in 1989 to 1991 and a Strong Heart Family Study (SHFS) cohort recruited in 1998 to 1999. The original and family cohorts together form the largest, multicenter, prospective epidemiological study of cardiovascular disease (CVD) in Native Americans/ American Indians. The study?s main objective is to examine the etiology and natural history of cardiovascular disease in Native Americans/American Indians. The study involves a partnership with 12 Tribal Nations who live in Arizona, Oklahoma, and the Dakotas.

NHLBI - National Heart Lung and Blood Institute

The Strong Heart Study (SHS) is a longitudinal observational study of two combined cohorts followed prospectively: the original SHS cohort recruited in 1989 to 1991 and a Strong Heart Family Study (SHFS) cohort recruited in 1998 to 1999. The original and family cohorts together form the largest, multicenter, prospective epidemiological study of cardiovascular disease (CVD) in Native Americans/ American Indians. The study?s main objective is to examine the etiology and natural history of cardiovascular disease in Native Americans/American Indians. The study involves a partnership with 12 Tribal Nations who live in Arizona, Oklahoma, and the Dakotas.

NHLBI - National Heart Lung and Blood Institute

The Strong Heart Study (SHS) is a longitudinal observational study of two combined cohorts followed prospectively: the original SHS cohort recruited in 1989 to 1991 and a Strong Heart Family Study (SHFS) cohort recruited in 1998 to 1999. The original and family cohorts together form the largest, multicenter, prospective epidemiological study of cardiovascular disease (CVD) in Native Americans/ American Indians. The study?s main objective is to examine the etiology and natural history of cardiovascular disease in Native Americans/American Indians. The study involves a partnership with 12 Tribal Nations who live in Arizona, Oklahoma, and the Dakotas.

NHLBI - National Heart Lung and Blood Institute

ABSTRACT Pulmonary arterial hypertension (PAH), a rare, debilitating and fatal disease for which there is currently no available cure. There is compelling evidence that NAD-dependent signaling via NAMPT is a novel and therapeutic target for PAH. To facilitate the translation of current in vivo and in vitro observations on the role of NAMPT dependent signaling in PAH pathobiology, this proposal will explore the hypothesis that the NAMPT/NAD signaling axis regulates physiologic, cellular and molecular pathways in PAH that result in pulmonary vascular remodeling. SA1 seeks to define the role of pulmonary artery endothelial cell NAMPT in the regulation on metabolic reprograming associated with the PH response. SA2 define the role of NAMPT in regulating mitochondrial dynamics in pulmonary artery endothelial cells. SA3 will seek discover and validate biochemical and genetic NAMPT-centric biomarkers of PAH susceptibility and prognosis.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY We propose to organize and conduct the Thirteenth (13th) Annual Pediatric Transplant and Cellular Therapy Consortium (PTCTC) Meeting at the NMDP, which houses an indoor arena located in Minneapolis, MN, on April 28th, 2026. A unique aspect of the Annual PTCTC Educational Meeting is that it is jointly held with the international American Society of Pediatric Hematology Oncology Conference (April 29-May 2, 2026) and includes a Combined Plenary Session, bringing pediatric hematology oncology professionals together from around the world. Hematopoietic cell transplantation (HCT) is a potentially curative therapy for many childhood illnesses. Basic, translational, and clinical research advances have significantly increased non-relapse mortality after HCT. The remarkable success is partly owed to the presentation, dissemination, and sharing of new knowledge at annual meetings. This 1-day program will invigorate the field of pediatric HCT. The theme of the 13th Annual PTCTC Educational Meeting will be “Select & Sustain: From Donor Choice, to Short Term Safety and Long-Term Recovery”. The meeting will focus on donor selection for HCT (a special focus of the NMDP) as well as short-term transplant-related complications and improving care for our long-term survivors in the years after treatments. The first session will provide the latest on HLA typing to select the optimal donor and provide updates on clinical trials that expand donor access/availability. A session focusing on acute transplant complications will include presentations and discussions on endothelial injury, special considerations for patients requiring care in the pediatric intensive care unit, and complications in those being treated for non-malignant disease. A third session will provide further insight into the care of long-term survivors following HCT and cellular therapy. Their unique medical needs require knowledge about potential long-term side effects and how to best identify and screen for these complications. Presentations will focus on the appropriate use of guideline-directed care, challenges in transitions of care as patients age or move from the treating center, and unique considerations for the malignant vs non-malignant patient populations. Finally, we will have a session dedicated to healthcare provider resilience and mentorship. The primary objectives include: I) review the “state of the science” in donor selection, access, and HLA typing, II) providing evidence-based guidelines to screen, recognize, and treat acute toxicities after HCT through standardized strategies that can be implemented irrespective of the treating institution; III) review the up-to-date recommendations in long-term survivorship care, IV) enhance the understanding of wellness through resilience and mentorship, and V) provide mechanisms to recognized to promote networking and collaboration of research and clinical trials involving pediatric HCT patients. The results of the 13th Annual PTCTC Educational Meeting will enhance our understanding of the basic, translational, and clinical state of the scientific research on the above noted topic areas, which will provide an opportunity and platform to engage young and senior clinicians and scientists to develop collaborative research.

NHLBI - National Heart Lung and Blood Institute

Summary Funding is requested for the registration fees and travel costs of invited speakers and discussion leaders as well as registration fee support for graduate students, postdocs, and early/mid- career scientists with an emphasis on first-time attendees at the 2026 12th Symposium on Hemostasis at the University of North Carolina (UNC) at Chapel Hill. The theme of the 2026 Symposium is novel perspectives on classically understood pathways. The program is designed to bring together experts to present their most recent cutting- edge findings centered on defining novel mechanisms and innovative therapeutic advances in hemostasis and thrombosis. Recent studies suggest that coagulation proteins and platelets are tied to numerous pathological processes through mechanisms both dependent and independent of their traditional roles in hemostasis and thrombosis. Our invited speakers will present their latest and emerging work across a spectrum of basic science and clinical topics where coagulation proteins and platelets play a functional role, including cancer, infection and immunity, acute injury, and pregnancy. Priority will be placed on highlighting both the role these proteins play as disease modifiers, as well as the utility of employing or targeting these factors for diagnosis and therapy. A major goal for the 12th Symposium on Hemostasis is highlighting the translation of basic research findings into the clinical practice. Over 80% of our invited speakers will be presenting at this conference for the first time, and 30% represent early career faculty. In addition to invited speakers and discussion leaders, attendees will be selected by invitation and from submitted applications. They will be chosen to represent a broad, interdisciplinary spectrum of research topics. Additional efforts will be committed to recruiting first-time attendees as speakers in the ‘Hot Topics’ session and as poster presenters. An intended strength of this meeting will be the interaction and networking of young scientists in the field with the discussion leaders and the speakers. Collectively, the specific aims for the 12th Symposium on Hemostasis are to: (i) provide an environment that facilitates lively and open discussions between early career, mid-career, and established scientists that fuels the process of scientific discovery in the hemostasis and thrombosis community; (ii) provide a platform of support for the careers of junior scientists, including predoctoral and postdoctoral trainees, to ensure growth of the field; (iii) promote collaborative and interdisciplinary scientific research that opens channels of long-term interaction and networking; and (iv) provide a mechanism for clinicians to earn continuing medical education credits in the areas of hemostasis, thrombosis, and hematology. Through these specific aims the 12th Symposium on Hemostasis will reveal the next chapter of discovery and innovation for hemostasis and thrombosis research while helping to establish and build on the collaborative relationships necessary to push the field forward.

NHLBI - National Heart Lung and Blood Institute

Staphylococcus aureus is the most common cause of lung infections in the US cystic fibrosis (CF) population, with nearly half (48.3%) of persons with CF testing positive for S. aureus in 2023. Testing for CF lung infections heavily relies upon the collection of sputum, but as CF care improves through the use of highly effective cystic fibrosis transmembrane conductance regulator therapy, the production of sputum has declined, though the risk of lung infections persists. Therefore, novel methods for diagnosing lung infections without sputum are urgently needed. Our goal is to develop highly sensitive and specific, non-invasive breath tests for the detection of S. aureus and other lung infections. The overall objective of this proposal is to develop biomarkers for S. aureus lung infections through the secondary analysis of breath volatilomics data and clinical metadata collected for the IMproving P. Aeruginosa deteCTion using Breath (IMPACT-Breath) clinical study. We hypothesize that breath biomarkers can detect S. aureus lung infections and discriminate them from other mono-infections and co-infections with > 80% accuracy. We will test this hypothesis via three Specific Aims: Aim 1: Identify biomarkers that differentiate breath samples from pwCF who are Staphylococcus aureus positive vs. negative. Using machine learning algorithms, we will build classification models that discriminate breath samples from subjects with new or chronic S. aureus infections (Sa+) vs. S. aureus negative (Sa-). Aim 2: Identify breath biomarkers that differentiate S. aureus vs. P. aeruginosa lung infections. P. aeruginosa is the second most common lung pathogen in the US CF population and in the IMPACT-Breath study cohort. Using the P. aeruginosa infection status from the IMPACT-Breath study, we will build classification models that discriminate breath samples from subjects infected with S. aureus vs. P. aeruginosa (Sa+ vs. Pa+). Aim 3: Identify breath biomarkers that differentiate S. aureus mono-infections from S. aureus-P. aeruginosa co-infections. Using IMPACT-Breath data, we will build classification models that discriminate breath samples from subjects with S. aureus mono-infections vs. S. aureus–P. aeruginosa co-infections (Sa+ vs. Sa+Pa+). The expected outcomes of this project are putative breath biomarkers for detecting S. aureus lung infections and estimates of their sensitivity and specificity, which will provide us with the necessary preliminary data to design a prospective clinical study to validate S. aureus biomarkers in the breath of pwCF.