Diversity Supplement Denzel Deo Omengan

多样性补充剂 Denzel Deo Omengan

基本信息

批准号：
10381108
负责人：
Guo Huang
金额：
$ 3.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2021-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381108
关键词：
Adult Animals Area Arrhythmia Automobile Driving Basal metabolic rate Biogenesis Biological Assay Biology Birth Cardiac Cardiac Myocytes Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Cessation of life Chemicals Cicatrix Cytokinesis DNA biosynthesis Data Development Diploidy Down-Regulation Endocrine system Evolution Family Dasypodidae Gene Expression Regulation Genes Genetic Growth Heart Heart Block High Prevalence Life Mammals Metabolic Pathway Mitochondria Mole Rats Molecular Mononuclear Mus Muscle Cells Mutant Strains Mice Myocardial Infarction Myrmecophagidae Natural regeneration Neonatal Newborn Infant Newts Nuclear Hormone Receptors Organ Organism Oxidative Stress Pathway interactions Patients Perinatal Pharmacology Phylogenetic Analysis Phylogeny Physiological Ploidies Process Rattus Reactive Oxygen Species Receptor Activation Regenerative capacity Reporting Research Role Signal Transduction Source Spiny Anteater Stimulus Testing Thyroid Function Tests Thyroid Hormones Thyroxine Tissues Up-Regulation Vertebrates Work Zebrafish base cardiac regeneration cardiogenesis comparative experimental study falls functional improvement hemodynamics hormonal signals hormone deficiency in vivo ischemic injury loss of function mouse model myocardial injury neonatal mice novel parent grant postnatal preservation regeneration potential regenerative tool transcriptome transcriptome sequencing

项目摘要

Project Summary/Abstract Most adult mammalian tissues and organs have very limited regenerative potential. In patients with a heart attack, the death and loss of heart muscle cells is irreversible and often results in permanent scarring and potentially life-threatening arrhythmias. In contrast, neonatal mice and adult zebrafish are able to rapidly regenerate their hearts. Genetic lineage-tracing experiments have revealed proliferation of pre-existing cardiomyocytes as the dominant mechanism to generate new muscle cells. However shortly after birth, the majority of cardiomyocytes in most mammalian species undergoes a last round of DNA replication without cytokinesis, become binucleated, and withdraw from the cell cycle. What physiological signals trigger mammalian cardiomyocyte perinatal binucleation and cell cycle arrest, and how these stimuli are differentially regulated in animals with distinct cardiac regenerative potentials are among the most long-standing questions in cardiomyocyte biology. Our preliminary observations from comparative analyses of cardiomyocytes across phylogeny, in vivo chemical screens of candidate pathways, together with functional studies in both mice and zebrafish suggest a critical role of the perinatal changes of endocrine systems in driving cardiomyocyte proliferative and regenerative potential loss in the mammalian heart. In this proposal, we plan to combine a novel cardiomyocyte quantification assay with state-of-art genetic tools to investigate the functions of nuclear hormone receptor activation in regulating cardiomyocyte proliferation during postnatal growth (Aim 1) and heart regeneration following myocardial injury (Aim 2). In addition, we will examine the underpinning cellular and molecular basis, and determine the function of novel downstream target genes in cardiomyocyte cell cycle control through gain- and loss-of-function approaches (Aim 3). Successful completion of the proposed work will thus reveal mechanisms underlying the loss of cardiomyocyte regenerative potential in ontogeny and phylogeny.

项目概要/摘要大多数成年哺乳动物组织和器官的再生潜力非常有限。对于心脏病患者攻击时，心肌细胞的死亡和损失是不可逆转的，通常会导致永久性疤痕和可能危及生命的心律失常。相比之下，新生小鼠和成年斑马鱼能够快速使他们的心重生。遗传谱系追踪实验揭示了先前存在的增殖心肌细胞作为产生新肌肉细胞的主要机制。然而出生后不久，大多数哺乳动物物种中的大多数心肌细胞在不进行最后一轮DNA复制的情况下进行胞质分裂，变成双核，并退出细胞周期。触发什么生理信号哺乳动物心肌细胞围产期双核和细胞周期停滞，以及这些刺激的差异在具有独特心脏再生潜力的动物中受到调节是最长期存在的问题之一心肌细胞生物学。我们对不同心肌细胞的比较分析的初步观察系统发育、候选途径的体内化学筛选以及小鼠和小鼠的功能研究斑马鱼表明内分泌系统的围产期变化在驱动心肌细胞方面发挥着关键作用哺乳动物心脏的增殖和再生潜力丧失。在本提案中，我们计划结合使用最先进的遗传工具进行新型心肌细胞定量测定，以研究核功能激素受体激活在出生后生长（目标 1）和心脏过程中调节心肌细胞增殖心肌损伤后的再生（目标 2）。此外，我们将检查基础细胞和分子基础，并确定心肌细胞周期中新型下游靶基因的功能通过功能获得和丧失的方法进行控制（目标 3）。成功完成拟议工作将从而揭示个体发育过程中心肌细胞再生潜力丧失的机制系统发育。