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: 10820376
• 负责人: Michaela Patterson
• 金额: $ 6.12万
• 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/10820376
• 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。在这里， 我们鉴定了两个新的候选基因，每个对CM细胞周期和倍性具有独特的影响。 此外，我们假设，已确定的基因将协同工作，以最大限度地提高性状效应，因此， 多因素的心脏再生方法是谨慎的。目标1将探索其第一个新的候选人， 在未损伤和梗死后环境中对心脏功能和CM细胞周期活性的独立影响。它 还将与Tnni 3 k结合进行测试。目标2将检查第二种新候选物对 CM倍性、细胞周期和心脏再生两者独立地和与Tnni 3 k组合。我们事先 GWAS研究证实CM倍体和心脏再生是依赖于多种细胞因子的复杂表型。 遗传位点在这里，我们使用遗传学方法在单个动物模型中调节多个候选基因 并且我们预期这种组合方法将增强CM增殖和心脏再生。