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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

基本信息

批准号：
10349456
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
项目类别：
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/10349456
关键词：
Ablation Address Adult Affect Animal Model Belief Birth Candidate Disease Gene Cardiac Myocytes Cardiovascular system Cell Cycle Cells Chromosomes Clinical Competence Complex Cytokinesis DNA biosynthesis Data Diploidy Evaluation Eye Color Failure Frequencies Genes Genetic Genetic Epistasis Heart Heart Injuries Height Impairment Individual Infarction Injury Intervention Knock-out Knockout Mice Knowledge Laboratories Mediating Mitotic Mononuclear Mouse Strains Mus Myocardial Myocardial Infarction Myocardial tissue Myocardium Natural regeneration Nature Other Genetics Outcome Patients Phase Phenotype Phosphotransferases Play Ploidies Polyploidy Process Proteins RNA Recovery of Function Regenerative response Role Seminal Testing Therapeutic Variant Work Zebrafish cardiac regeneration combinatorial design gene function genetic approach genome wide association study genomic locus heart function innovation loss of function novel overexpression postnatal regenerative repaired senescence trait

项目摘要

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/摘要心血管领域的教条认为，成年哺乳动物的心脏本质上是非再生的，这种再生的失败主要归因于大多数有丝分裂后和多倍体的性质心肌细胞(CMS)。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CMS的一个特权亚群，具有避免了这种增殖性衰老。这一属性赋予了重新进入细胞周期和再生心肌组织。我们最近在小鼠身上的研究表明，MNDCM和心脏再生能力是受复杂基因影响的两个相互关联和可变的特征个人背景。换句话说，与长期存在的信念相反，一些人可以登上在受到侮辱后有意义的再生反应，如心肌梗塞。然后我们提取了一个基因组- 广泛的关联策略，以确定与观察到的变异相关的基因。从这个分析来看，我们发现TNNI3K是通过抑制细胞质分裂来调节CM衰老的候选基因之一。这里, 我们发现了两个新的候选基因，每个基因都对CM的细胞周期和倍性有独特的影响。此外，我们假设已识别的基因将协同工作以最大化性状效应，因此心脏再生的多因素方法是谨慎的。Aim 1将探索ITS的第一个新候选者在未损伤和梗死后环境中对心功能和CM细胞周期活动的独立影响。它还将与TNNI3K一起进行测试。目标2将考察第二个新候选人对 CM的倍性、细胞周期和心脏再生均独立存在，并与TNNI3K联合应用。我们的前辈 Gwas研究证实，CM倍性和心脏再生是依赖于多个遗传基因。在这里，我们使用遗传方法在单个动物模型中调节多个候选基因我们预计，这种组合方法将促进CM的增殖和心脏再生。