Analysis of Single Cell Transcriptomics and Cardiac Metabolism in Heart Failure with Preserved Ejection Fraction

保留射血分数的心力衰竭的单细胞转录组学和心脏代谢分析

• 批准号: 10571526
• 负责人: Virginia Shalkey Hahn
• 金额: $ 19.82万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571526
• 关键词: Address; Affect; American; Animal Model; Autophagocytosis; Bioinformatics; Biological; Biological Assay; Biopsy; Blood specimen; Cardiac Myocytes; Cardiology; Cardiometabolic Disease; Cardiovascular system; Caring; Cells; Clinical; Clinical Trials; Coronary sinus structure; Data; Depressed mood; Development; Development Plans; Disease; EFRAC; Endothelial Cells; Environment; Enzymes; Exclusion; Exhibits; Extracellular Matrix; Fatty Acids; Fellowship; Female; Fibroblasts; Generations; Genes; Glucose; Goals; Heart; Heart failure; Heterogeneity; Human; Hypertrophy; Immune; Inflammatory; Institution; International; Investments; K-Series Research Career Programs; Knowledge; Learning; Left Ventricular Hypertrophy; Master of Science; Measures; Medical; Medicine; Mentors; Metabolic; Metabolism; Mission; Modeling; Molecular; Morbid Obesity; Myocardial; Myocardium; National Heart, Lung, and Blood Institute; Natriuretic Peptides; Nuclear RNA; Obesity; Oxidative Phosphorylation; Pathway interactions; Patients; Pattern; Phenotype; Physicians; Positioning Attribute; Postdoctoral Fellow; Precision therapeutics; Prevalence; Proteins; Proteomics; Protocols documentation; Publishing; Reporting; Research; Research Personnel; Risk Factors; Role; Sampling; Scientist; Serum; Sodium; Subgroup; Syndrome; Testing; Tissue Sample; Tissues; Training; Transcript; Translational Research; United States National Institutes of Health; Universities; Ventricular Remodeling; Virginia; Woman; Work; career; career development; cell type; clinical phenotype; clinically relevant; cohort; comorbidity; comparison control; effective therapy; exercise capacity; experience; fatty acid oxidation; heart dimension/size; heart metabolism; hemodynamics; human RNA sequencing; human subject; human tissue; imaging study; in vivo; individualized medicine; inhibitor; insight; medical schools; metabolic profile; metabolomics; multiple omics; non-invasive imaging; novel therapeutics; oxidation; peripheral blood; preservation; professor; programs; protein expression; single cell analysis; single nucleus RNA-sequencing; skills; stem; success; symporter; transcriptomics; uptake

PROJECT SUMMARY Virginia Shalkey Hahn, MD is an Assistant Professor of Medicine and heart failure cardiologist in the Division of Cardiology at Johns Hopkins University. Her long-term goal is to become an independent investigator harnessing bioinformatics to answer clinically relevant questions in the fields of heart failure and cardiometabolic disease. She focuses on the intersection of cardiometabolic disease and heart failure due to the rising prevalence of obesity and its prominent role in Heart Failure with Preserved Ejection Fraction (HFpEF). HFpEF is a common disease with limited effective therapies due to its heterogeneity and limited analysis of human tissue. Her prior work used myocardial transcriptomics to create HFpEF subgroups that had distinct clinical profiles, one of which was composed of women with normal natriuretic peptides, a group that was excluded from most all prior and even recent positive clinical trials for HFpEF. The Specific Aims of the current proposal are to 1) determine differences in myocardial cell composition and cell cluster-specific transcriptomics in HFpEF using single nuclei RNA sequencing, 2) define the myocardial metabolic profiles of HFpEF using multi-omic analysis of endomyocardial biopsy tissue, and 3) measure differences in metabolite uptake/secretion by the heart in HFpEF using coronary sinus sampling. The significance of the proposal stems from the use of human tissue with strong clinical phenotyping, and its likelihood to spawn precision therapies for HFpEF that target unique abnormalities in distinct subgroups, particularly subsets of female patients who are traditionally excluded from clinical trials. Dr. Hahn has assembled a world-class mentoring team well- poised to complete the research and training aims of the proposal. The primary mentor, Dr. David A. Kass, is an internationally renowned cardiovascular scientist with >36 years of experience training several generations of physician-scientists. He has extensive experience serving as primary mentor for NIH career development awards. Co-mentors Dr. Patrick Ellinor and Dr. Kavita Sharma have expertise in cardiovascular bioinformatics, translational research, and HFpEF. Collaborators add expertise in proteomics, metabolism, and bioinformatics. The work is performed in the fertile academic environment at the Johns Hopkins University School of Medicine, where the Division of Cardiology demonstrates a clear commitment and investment in Dr. Hahn's research career. The career development plan focuses on development of a formal bioinformatics skillset through hands-on analysis and a Master of Science degree in Bioinformatics. These skills will distinguish Dr. Hahn from her mentors as an independent investigator with a unique niche in bioinformatics and heart failure. Dr. Hahn and her mentoring team are well poised to address the most pressing knowledge gaps in HFpEF and make major breakthroughs toward better care for our patients.

项目概要 Virginia Shalkey Hahn 医学博士是医学助理教授和心力衰竭心脏病专家 约翰·霍普金斯大学心脏病学。她的长期目标是成为一名独立调查员 利用生物信息学回答心力衰竭领域的临床相关问题 心脏代谢疾病。她专注于心脏代谢疾病和心力衰竭的交叉领域 肥胖患病率的上升及其在射血分数保留的心力衰竭中的重要作用 （HFpEF）。 HFpEF 是一种常见疾病，由于其异质性和有限性，有效的治疗方法有限。 人体组织分析。她之前的工作使用心肌转录组学创建了 HFpEF 亚组，该亚组具有 不同的临床特征，其中一个由利尿钠肽正常的女性组成，这一组 被排除在大多数之前甚至最近的 HFpEF 阳性临床试验之外。具体目标 目前的建议是 1) 确定心肌细胞组成和细胞簇特异性的差异 使用单核 RNA 测序在 HFpEF 中进行转录组学，2) 定义心肌代谢谱 HFpEF 使用心内膜心肌活检组织的多组学分析，以及 3) 测量代谢物的差异 使用冠状窦取样测定 HFpEF 中心脏的摄取/分泌。该提案的意义源于 来自使用具有强大临床表型的人体组织及其产生精准疗法的可能性 针对 HFpEF，针对不同亚组中的独特异常，特别是女性患者亚组 传统上被排除在临床试验之外。哈恩博士组建了一支世界一流的指导团队—— 准备完成该提案的研究和培训目标。主要导师 David A. Kass 博士是 国际知名心血管科学家，拥有超过 36 年的培训几代人的经验 医生科学家。他拥有担任 NIH 职业发展主要导师的丰富经验 奖项。共同导师 Patrick Ellinor 博士和 Kavita Sharma 博士拥有心血管生物信息学方面的专业知识， 转化研究和 HFpEF。合作者增加了蛋白质组学、新陈代谢和生物信息学方面的专业知识。 这项工作是在约翰·霍普金斯大学医学院肥沃的学术环境中进行的， 心脏病科表现出对哈恩博士研究的明确承诺和投资 职业。职业发展计划的重点是通过以下方式发展正式的生物信息学技能 动手分析和生物信息学理学硕士学位。这些技能将使哈恩博士脱颖而出 作为一名独立研究者，她在生物信息学和心力衰竭领域拥有独特的地位。博士。 Hahn 和她的指导团队已准备好解决 HFpEF 和 取得重大突破，为我们的患者提供更好的护理。