Genetic interactions and multifactorial genetics mediate myocardial regeneration

遗传相互作用和多因素遗传学介导心肌再生

• 批准号: 10381182
• 负责人: Michaela Patterson
• 金额: $ 3.7万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-11 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381182
• 关键词: Adult; Award; Belief; Candidate Disease Gene; Cardiac Myocytes; Cardiovascular system; Cell Cycle; Competence; Complex; Cytokinesis; Diploidy; Eye Color; Failure; Frequencies; Genes; Genetic; Heart; Heart Injuries; Height; Individual; Injury; Knowledge; Mediating; Mitotic; Modeling; Mononuclear; Mus; Myocardial; Myocardial Infarction; Myocardial tissue; Myocardium; Natural regeneration; Nature; Neonatal; Outcome; Parents; Patients; Ploidies; Polyploidy; Process; Recovery of Function; Regenerative response; Therapeutic; Variant; Work; cardiac regeneration; design; experimental study; genome wide association study; loss of function; parent grant; regeneration model; repaired; senescence; trait

PROJECT SUMMARY/ABSTRACT Dogma in the cardiovascular field argues that the adult mammalian heart is essentially non-regenerative and that this failure to regenerate is primarily attributed to the post-mitotic and polyploid nature of most cardiomyocytes (CMs). Multiple pieces of evidence now support the idea that within the adult mammalian myocardium, mononuclear diploid cardiomyocytes (MNDCMs) are a privileged subpopulation of CMs that have avoided this proliferative senescence. This attribute confers a unique capacity to re-enter the cell cycle and regenerate myocardial tissue. Our recent work in mice demonstrates that the frequency of MNDCMs and the competence to regenerate one's heart are two interlinked and variable traits influenced by the complex genetic background of an individual. In other words, contrary to longstanding beliefs, some individuals can mount a meaningful regenerative response after an insult, such as a myocardial infarction. We then took a genome- wide association strategy to identify the genes associated with the observed variation. From this analysis, we identified Tnni3k as one candidate that regulates CM senescence by inhibiting cytokinesis, specifically. The parent R01, examines two additional candidate genes that arose from the original screen, each of which has a unique effect on CM cell cycle and ploidy. Experiments proposed in the parent grant investigate both candidates for their effects on CM ploidy, cell cycle, and post-injury outcomes, specifically in the context of an adult injury setting. This Diversity Supplement proposes additional experiments which will strengthen the second aim of the parent award and provide complementary evidence in support of candidate gene, Runx1. Specifically, using the same gain- and loss-of-function genetic mice from the parent award, we extend our analysis of Runx1 into an injury model that displays substantial CM proliferation and competence for myocardial regeneration, the neonatal regeneration model. Thus, allowing us to examine the effect of Runx1 in both a pro- and non-regenerative model of heart injury.

项目总结/摘要 心血管领域的教条认为，成年哺乳动物的心脏基本上是不可再生的， 这种再生的失败主要归因于大多数细胞的有丝分裂后和多倍体性质， 心肌细胞（CM）。现在有多项证据支持这一观点，即在成年哺乳动物体内， 心肌，单核二倍体心肌细胞（MNDCM）是CM的特权亚群，具有 避免了这种增殖性衰老。该属性赋予重新进入细胞周期的独特能力， 再生心肌组织。我们最近在小鼠中的研究表明，MNDCM的频率和 再生心脏的能力是两个相互关联的可变特征，受复杂的遗传因素的影响， 个人的背景。换句话说，与长期以来的信念相反，一些人可以安装一个 损伤后有意义的再生反应，如心肌梗死。我们取了一个基因组- 广泛关联策略，以识别与观察到的变异相关的基因。通过分析，我们 将Tnni 3 k鉴定为通过抑制胞质分裂来调节CM衰老的一种候选物。的 亲本R 01，检查从原始筛选中产生的两个额外的候选基因，每个候选基因具有一个 对CM细胞周期和倍性的独特作用。在父母补助金中提出的实验调查了这两种情况。 候选人对CM倍性，细胞周期和损伤后结果的影响，特别是在 成人伤害设置。该多样性补充建议进行更多的实验，以加强 父母奖的第二个目的，并提供支持候选基因Runx 1的补充证据。 具体来说，使用来自父母奖励的相同的功能获得和功能丧失遗传小鼠，我们扩展了我们的 分析Runx 1进入显示大量CM增殖和能力的损伤模型， 新生儿心肌再生模型。因此，允许我们检查Runx 1在 这两种模型都是心脏损伤的促进再生和非再生模型。