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

• 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
• 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

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.

项目摘要/摘要 心力衰竭（HF）是发病率和死亡率的日益原因。尽管有最好的治疗方法， 对于许多HF患者而言，预后仍然很差，强调了对新的HF疗法的临床需求。 该杰出的调查员奖申请的灵感来自于观察到锻炼保护 心脏，促进心肌细胞（CM）生存和增殖，同时减少纤维化和炎症。然而 我们对负责任机制以及是否可以热探索它们的负责机制。这里， 我计划利用NHLBI R35杰出的长期支持和科学灵活性 调查人员奖，以阐明运动心脏益处的细胞和分子基础 验证临床前模型中潜在的新治疗靶标。我们发现，尽管运动和 病理压力既诱导心脏肥大，这是运动诱导的机制 肥大在很大程度上是不同的，而不是导致后遗症，而是矛盾地保护了心脏 （Cell，2010年）。我们还发现，运动大大增强了成人的内源性心肌发生 哺乳动物心（自然通讯，2018年）。在某些情况下，模仿运动中看到的变化不仅 预防但可以逆转建立的HF（Science Trans. Med。，2019）。在这里，我们提出了一个广泛的计划 要描绘运动的细胞和分子效应，请定义介导的机械途径 锻炼的心肌生成和其他好处，并探索这些途径的翻译潜力 在临床前模型中。描述心脏对心肌细胞运动的适应性反应和非 - 心肌细胞将使用一系列无偏见的工具，包括单核RNA- 测序（SNRNA-SEQ），散装RNA-SEQ和用于转座酶可访问的染色质（ATAC-SEQ）的测定。 SnRNA-Seq将洞悉基因表达的细胞谱系特异性变化，以响应运动 随着时间的流逝，这种方法将与谱系特异性的增益和功能丧失模型相结合，以帮助 定义细胞类型之间的串扰。几种标签工具将用于促进分裂的识别 SnRNA-Seq研究中的CMS研究介绍了此动态过程并测试特定的假设 CMS和/或宽容环境的亚群是心脏病发生的。统计上 使用相关的体外细胞将对强大的候选者进行保护和心肌生成效应 培养和体内斑马鱼模型。最有希望的是在临床前鼠和猪中研究 揭示新的生物学途径并开发新的治疗方法的模型。 R35机制 独特地提供了支持拟议的无偏见的灵活性和时间框架， 生物信息学分析和独特的动物模型的产生。成功完成该计划 将促进我们对心脏的理解和心脏运动的有益作用，而 描述有可能减轻心力衰竭的途径，从而满足紧迫的临床需求。