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: 10563217
• 负责人: Michaela Patterson
• 金额: $ 46.42万
• 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/10563217
• 关键词: Ablation; Address; Adult; Affect; Animal Model; Belief; Birth; Candidate Disease Gene; Cardiac Myocytes; Cardiovascular system; Cell Cycle; Cells; Chromosomes; Classification; Clinical; Competence; Complex; Cytokinesis; DNA biosynthesis; Data; Diploidy; Evaluation; Eye Color; Failure; Frequencies; Genes; Genetic; Genetic Epistasis; HDAC7 histone deacetylase; Heart; Heart Injuries; Height; Impairment; Individual; Infarction; Injury; Intervention; Knock-out; Knockout Mice; Knowledge; Laboratories; Mediating; Mononuclear; Mouse Strains; Mus; Myocardial; Myocardial Infarction; Myocardial tissue; Myocardium; Natural regeneration; Nature; Other Genetics; Outcome; Patients; Phase; Phenotype; Phosphotransferases; Play; Ploidies; Polyploidy; Postdoctoral Fellow; Process; Proliferating; Proteins; RNA; Recovery of Function; Regenerative response; Role; Seminal; Testing; Therapeutic; Variant; Work; Zebrafish; candidate identification; cardiac regeneration; cell regeneration; combinatorial; design; gene function; genetic approach; genome wide association study; genomic locus; heart function; innovation; loss of function; novel; overexpression; permissiveness; postmitotic; postnatal; regenerative; 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. Here, we identify two new candidate genes each of which has a unique effect on CM cell cycle and ploidy. Furthermore, we hypothesize that identified genes will work cooperatively to maximize the trait effect, thus a multifactorial approach to heart regeneration is prudent. Aim 1 will explore the first novel candidate for its independent effect on heart function and CM cell cycle activity in both uninjured and post-infarction settings. It will also be tested in combination with Tnni3k. Aim 2 will examine the effect of the second novel candidate on CM ploidy, cell cycle, and heart regeneration both independently and in combination with Tnni3k. Our prior GWAS study affirms that CM ploidy and cardiac regeneration are complex phenotypes relying on multiple genetic loci. Here, we use genetic approaches to modulate multiple candidate genes in a single animal model and we anticipate that this combinatorial approach will potentiate CM proliferation and cardiac regeneration.

项目摘要/摘要 心血管领域中的教条认为，成年哺乳动物心脏本质上是非再生的，并且 这种失败的重新生成主要归因于大多数的有丝分裂后和多倍体性质 心肌细胞（CMS）。现在有多个证据支持成年哺乳动物内的想法 心肌，单核二倍体心肌细胞（MNDCMS）是具有具有的特权亚群 避免了这种扩散的衰老。该属性赋予重新进入单元周期的独特能力和 再生心肌组织。我们最近在小鼠中的工作表明MNDCMS和 再生一个人的心脏的能力是两个相互联系和可变特征，受复杂遗传的影响 个人的背景。换句话说，与长期的信念相反，有些人可以安装 侮辱后的有意义的再生反应，例如心肌梗塞。然后，我们采用了一个基因组 - 识别与观察到的变异相关的基因的广泛关联策略。从这个分析，我们 将TNNI3K鉴定为一种通过抑制细胞因子（特别是抑制细胞因子）来调节CM衰老的候选者。这里， 我们识别两个新的候选基因，每个候选基因对CM细胞周期和倍增感具有独特的影响。 此外，我们假设确定的基因将合作起作用以最大化特征效应，从而 多因素的心脏再生方法是审慎的。 AIM 1将探索第一个小说候选人 在未受伤和进攻后设置中对心脏功能和CM细胞周期活性的独立影响。它 还将与TNNI3K结合进行测试。 AIM 2将检查第二个小说候选人对 CM倍性，细胞周期和心脏再生是独立并与TNNI3K结合的。我们的先验 GWAS研究确认，CM倍性和心脏再生是复杂的表型，依靠多个 遗传基因座。在这里，我们使用遗传方法来调节单个动物模型中的多个候选基因 我们预计这种组合方法将增强CM的增殖和心脏再生。