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: 10322189
• 负责人: ANTHONY ROSENZWEIG
• 金额: $ 90.95万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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/10322189
• 关键词: Adult; Affect; Animal Model; Award; Bioinformatics; Biological; Biological Assay; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Culture Techniques; Cell Lineage; Cell Nucleus; 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; Public Health; Research; Research Personnel; Science; Small Nuclear RNA; Stress; Testing; Therapeutic; Time; Transposase; Treatment Failure; Work; Zebrafish; cell type; flexibility; heart cell; in vivo; insight; loss of function; meetings; mortality; mouse model; new therapeutic target; novel therapeutic intervention; porcine model; pre-clinical; prevent; programs; response; 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.

项目概要/摘要 尽管有最好的治疗方法，但心力衰竭（HF）是发病率和死亡率日益增加的原因。 许多心力衰竭患者的预后仍然较差，这凸显了对新的心力衰竭疗法的临床需求尚未得到满足。 这项杰出研究者奖申请的灵感来自于运动可以保护身体的观察结果 心脏，促进心肌细胞（CM）存活和增殖，同时减少纤维化和炎症。 我们对其中的机制以及它们是否可以用于治疗了解甚少。 我计划利用 NHLBI R35 Outstanding 提供的长期支持和科学灵活性 研究者奖旨在阐明运动对心脏益处的细胞和分子基础，并 我们在临床前模型中验证了潜在的新治疗靶点。 病理应激均可诱发心肌肥厚，其机制是运动诱发的 肥厚在很大程度上是不同的，并且不但不会导致不良后遗症，反而可以保护心脏 （Cell，2010）我们还发现运动可以显着增强成人的内源性心肌生成。 哺乳动物心脏（Nature Comm.，2018）在某些情况下，不仅模仿运动中看到的变化。 预防但可以逆转已发生的心衰（Science Transl. Med.，2019）。在这里，我们提出了一个广泛的计划。 描述运动的细胞和分子效应，定义介导的机制途径 心肌生成和运动的其他益处，并探索这些途径的转化潜力 在临床前模型中描述心脏对心肌细胞和非心肌细胞运动的适应性反应。 心肌细胞，将采用一系列公正的发现工具，包括单核 RNA- 测序 (snRNA-seq)、批量 RNA-seq 和转座酶可及染色质分析 (ATAC-seq)。 snRNA-seq 将深入了解运动后基因表达的细胞谱系特异性变化 随着时间的推移，这种方法将与谱系特定的功能获得和丧失模型相结合，以帮助 定义细胞类型之间的串扰将使用多种标记工具来促进分裂的识别。 snRNA-seq 研究中的 CM 旨在描述这一动态过程并测试特定的假设 从统计学上讲，心肌发生需要 CM 亚群和/或允许的环境。 将使用相关体外细胞筛选稳健候选者的保护性和心肌生成作用 最有希望的研究将在临床前小鼠和猪身上进行。 模型来发现新的生物学途径并开发新的治疗方法。 独特地提供了支持拟议的公正发现和所需的灵活性和时间框架 生物信息分析和独特动物模型的生成成功完成该计划。 将增进我们对心肌发生和运动对心脏有益影响的理解，同时 描绘出有可能减轻心力衰竭的途径，从而满足紧迫的临床需求。