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Understanding the Cardiac Benefits of Exercise at the Cellular and Molecular Level

从细胞和分子水平了解运动对心脏的益处

基本信息

批准号：
10889616
负责人：
ANTHONY ROSENZWEIG
金额：
$ 84.75万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10889616
关键词：
Adult Affect Animal Model Award Bioinformatics Biological Biological Assay Cardiac Cardiac Myocytes Cardiovascular Diseases Cell Culture Techniques Cell Lineage Cells Chromatin Clinical Environment Exercise Fibrosis Gene Expression Generations Heart Heart Diseases Heart Hypertrophy Heart failure Hypertrophy In Vitro Inflammation Label Mediating Modeling Molecular Morbidity - disease rate National Heart, Lung, and Blood Institute Nature Pathologic Pathway interactions Patients Pre-Clinical Model Process Prognosis Proliferating Public Health Research Research Personnel Science Stress Testing Therapeutic Time Transposase Treatment Failure Work Zebrafish cell type flexibility gain of function heart cell in vivo insight loss of function meetings mortality mouse model new therapeutic target novel therapeutic intervention permissiveness porcine model pre-clinical prevent programs response single nucleus RNA-sequencing tool transcriptome sequencing translational potential

项目摘要

Project Summary/Abstract Heart failure (HF) is a growing cause of morbidity and mortality. Despite the best available treatments, prognosis remains poor for many HF patients underscoring the unmet clinical need for new HF therapies. This Outstanding Investigator Award application is inspired by the observation that exercise protects the heart, promoting cardiomyocyte (CM) survival and proliferation while reducing fibrosis and inflammation. Yet we understand little of the responsible mechanisms and whether they can be exploited therapeutically. Here, I plan to leverage the longer-term support and scientific flexibility afforded by the NHLBI R35 Outstanding Investigator Award to illuminate the cellular and molecular basis of the cardiac benefits of exercise and to validate potential new therapeutic targets in preclinical models. We discovered that although exercise and pathological stress both induce cardiac hypertrophy, the mechanisms underlying exercise-induced hypertrophy are largely distinct and, rather than leading to adverse sequelae, paradoxically protect the heart (Cell, 2010). We also found that exercise dramatically enhances endogenous cardiomyogenesis in the adult mammalian heart (Nature Comm., 2018). In some cases, mimicking the changes seen in exercise not only prevents but can reverse established HF (Science Transl. Med., 2019). Here we propose a broad program to delineate the cellular and molecular effects of exercise, define the mechanistic pathways mediating cardiomyogenesis and other benefits of exercise, and explore the translational potential of these pathways in preclinical models. To describe the heart’s adaptive response to exercise in cardiomyocytes and non- cardiomyocytes, a range of unbiased discovery tools will be employed including single nucleus RNA- sequencing (snRNA-seq), bulk RNA-seq, and Assay for Transposase-Accessible Chromatin (ATAC-seq). snRNA-seq will provide insight into cell lineage-specific changes in gene expression in response to exercise over time, and this approach will be combined with lineage-specific gain- and loss-of-function models to help define crosstalk between cell types. Several labeling tools will be used to facilitate identification of dividing CMs in snRNA-seq studies to profile this dynamic process and test the hypotheses that specific subpopulations of CMs and/or permissive environments are required for cardiomyogenesis. Statistically robust candidates will be screened for protective and cardiomyogenic effects using relevant in vitro cell culture and in vivo zebrafish models. The most promising will be studied in preclinical murine and porcine models to uncover new biological pathways and develop new therapeutic approaches. The R35 mechanism uniquely provides the flexibility and timeframe required to support the proposed unbiased discovery and bioinformatic analyses and the generation of unique animal models. Successful completion of this program will advance our understanding of cardiomyogenesis and the beneficial effects of exercise in the heart, while delineating pathways with the potential to mitigate heart failure, thus meeting a pressing clinical need.

项目总结/文摘