The complex genetics of heart regeneration

心脏再生的复杂遗传学

• 批准号: 9891094
• 负责人: Henry M Sucov
• 金额: $ 52.1万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-14 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891094
• 关键词: Abbreviations; Adult; Alleles; Biological; Birth; Cardiac Myocytes; Cardiac conduction system; Cell Cycle; Cell division; Cells; Competence; Complex; Complex Genetic Trait; Data; Diploidy; Disease; Electrocardiogram; Elements; Embryo; Embryonic Heart; Etiology; Event; Frequencies; Functional disorder; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Heart; Heart Injuries; Heart failure; Human; Hybrids; Inbred Mouse; Individual; Infarction; Injury; Knockout Mice; Lead; Life; Link; Maps; Methodology; Modeling; Mononuclear; Mouse Strains; Mus; Muscle Cells; Muscular Atrophy; Mutation; Natural regeneration; Neonatal; Outcome; Oxidative Stress; Pathology; Patients; Phenotype; Phosphotransferases; Plant Roots; Polyploidy; Population; Process; Publications; Recovery of Function; Role; System; Therapeutic; Time; base; biological adaptation to stress; cardiac regeneration; cardiogenesis; cell type; clinically significant; cost; genetic testing; genome wide association study; heart function; improved; insight; interest; lead candidate; loss of function; muscle regeneration; postnatal; postnatal period; predictive modeling; regenerative; trait

Project Summary Shortly after birth, most mammalian cardiomyocytes (CMs) become postmitotic and nonregenerative, concurrent with becoming polyploid (either binucleated or mononuclear tetraploid). What controls this process has been unknown. As a result, though, it is generally thought that the adult heart has too little regenerative capacity to appreciably recover after injury. A subpopulation of mononuclear diploid CMs (MNDCMs), thought to be very small in number, persists in the heart through adulthood and is a candidate cell type to support endogenous heart regeneration. Using a wholly new conceptualization, we demonstrated in inbred mice that the percentage of MNDCMs in the adult heart, and the degree of functional recovery and of CM proliferation after adult heart injury, are both highly variable traits subject to the combined influence of multiple polymorphic genes. We identified and confirmed the CM- specific kinase Tnni3k as one such gene with polymorphic alleles that influence variability in the adult level of MNDCMs and thereby in the level of CM regeneration after adult infarction. Using this new understanding, the focus of this project is to elucidate the processes that cause CMs to become polyploid and postmitotic, and the consequences of these processes. In Aim 1, we will dissociate the two roles of Tnni3k in the natural neonatal heart after birth and in the adult heart following injury; we propose that these are related but independent and both relevant to the outcome after adult injury. In Aim 2, we propose to identify two new genes that also influence how CMs remain proliferative or become postmitotic, and to confirm our insights related to the regenerative capacity of MNDCMs. In Aim 3, we explore an unexpected influence of Tnni3k in the proper function of the cardiac conduction system (the electrical system of the heart), and how this role relates to the process of heart regeneration. In Aim 4, we invoke a mechanistic understanding to unify these observations of CM regeneration and conduction. The conceptual significance of this project is transformational: rather than heart injury resulting inexorably in declining heart function as is currently believed, some individuals may have substantial regenerative ability depending on their genetic and cellular composition. Furthermore, these insights might be developed for therapeutics to improve heart regeneration in all patients regardless of their genetic background. And finally, this project might explain why the mammalian heart transitions in most individuals to become mostly postmitotic in the postnatal period, even at the cost of loss of regenerative ability.

项目摘要 出生后不久，大多数哺乳动物心肌细胞（CM）成为有丝分裂后， 非再生，同时变为多倍体（双核或单核 四倍体）。是什么控制了这个过程一直是未知的。因此，一般来说， 我认为成年人的心脏再生能力太小，在心脏衰竭后无法明显恢复。 损伤单核二倍体CMs（MNDCMs）的一个亚群，被认为是非常小的， 数量，持续在心脏通过成年期，是一个候选细胞类型，以支持 内源性心脏再生使用全新的概念，我们在 结果表明，MNDCMs在成年小鼠心脏中所占的百分比，以及MNDCMs的功能程度， 成年心脏损伤后CM的恢复和增殖，都是高度可变的性状， 多个多态性基因的联合影响。我们确认了CM- 特异性激酶Tnni 3 k作为一种这样的基因，其具有多态性等位基因， 成年MNDCMs的水平，从而在成年梗死后CM再生的水平。 利用这种新的理解，这个项目的重点是阐明导致 CM变成多倍体和有丝分裂后，以及这些过程的后果。在目标1中， 我们将分离Tnni 3 k在出生后的自然新生儿心脏和在成人心脏中的两种作用 我们认为，这些是相关的，但独立的，都与 成年人受伤后的结果。在目标2中，我们提出了两个新的基因， 影响CM如何保持增殖或成为有丝分裂后，并确认我们的见解 与MNDCM的再生能力有关。在目标3中，我们探索了一种意想不到的影响 Tnni 3 k在心脏传导系统（心脏的电系统）的正常功能中的作用 心脏），以及这种作用与心脏再生过程的关系。在目标4中，我们调用 统一CM再生和传导的这些观察的机制理解。 这个项目的概念意义是变革性的：而不是心脏损伤导致的 正如目前所认为的那样，心脏功能的下降是不可避免的，有些人可能有 基本的再生能力取决于他们的基因和细胞组成。 此外，这些见解可能会发展为治疗，以改善心脏再生 在所有患者中，无论其遗传背景如何。最后，这个项目也许可以解释为什么 大多数哺乳动物的心脏在有丝分裂后转变为有丝分裂后的心脏。 即使以丧失再生能力为代价。