权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
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
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/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

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.

项目总结/文摘