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

项目摘要 Virginia Shalkey Hahn，医学博士，医学助理教授，心力衰竭心脏病专家， 约翰霍普金斯大学的心脏病学。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点， 肥胖患病率的上升及其在射血分数保留性心力衰竭中的突出作用 （HFpEF）。HFpEF是一种常见疾病，由于其异质性和局限性， 分析人体组织。她先前的工作使用心肌转录组学来创建HFpEF亚组， 不同的临床特征，其中一组由正常利钠肽的女性组成， 从大多数之前甚至最近的HFpEF阳性临床试验中排除。的具体目标 目前的建议是：1）确定心肌细胞组成和细胞簇特异性 使用单核RNA测序的HFpEF转录组学，2）确定 使用肌内膜活检组织的多组学分析的HFpEF，和3）测量代谢物 使用冠状窦采样的HFpEF中心脏的摄取/分泌。该提案的重要性源于 从使用具有强大临床表型的人体组织，以及其产生精确疗法的可能性， 对于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。哈恩博士组建了一个世界级的指导团队， 准备完成该提案的研究和培训目标。主要导师，大卫博士A。卡斯群岛 国际知名的心血管科学家，拥有超过36年的经验，培养了几代人 物理学家和科学家他拥有丰富的经验，担任NIH职业发展的主要导师 奖共同导师帕特里克Ellinor博士和Kavita Sharma博士具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、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， 心脏病科在哈恩博士的研究中表现出明确的承诺和投资 事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硕士学位。这些技能将使哈恩博士 作为一名独立的研究者，她在生物信息学和心力衰竭方面有着独特的优势。博士 Hahn和她的指导团队已经做好准备，以解决HFpEF中最紧迫的知识差距， 在更好地照顾病人方面取得重大突破。

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.