Diversity Supplement Denzel Deo Omengan

多样性补充剂 Denzel Deo Omengan

• 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
• 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

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.

项目总结/摘要 大多数成年哺乳动物的组织和器官具有非常有限的再生潜力。在有心脏的病人中 心肌细胞的死亡和损失是不可逆的，通常会导致永久性疤痕， 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迅速 使他们的心重生。遗传谱系追踪实验显示， 心肌细胞作为产生新的肌肉细胞的主导机制。出生后不久， 大多数哺乳动物物种中的大多数心肌细胞经历最后一轮DNA复制， 细胞质分裂，变成双核，并退出细胞周期。什么生理信号触发了 哺乳动物心肌细胞围产期双核和细胞周期停滞，以及这些刺激是如何区别 在具有不同心脏再生潜力的动物中调节是最长期存在的问题之一， 心肌细胞生物学我们通过对不同年龄组的心肌细胞进行比较分析， 胚胎发育，候选途径的体内化学筛选，以及小鼠和 斑马鱼提示围产期内分泌系统的变化在驱动心肌细胞 哺乳动物心脏的增殖和再生潜力丧失。在本提案中，我们计划将联合收割机 一种新的心肌细胞定量分析与国家的最先进的遗传工具，以研究核的功能， 激素受体激活在出生后生长和心脏中调节心肌细胞增殖（Aim 1） 心肌损伤后的再生（目的2）。此外，我们将研究基础细胞和 分子基础，并确定新的下游靶基因在心肌细胞周期中的功能 通过功能增益和功能丧失方法进行控制（目标3）。顺利完成拟议工作将 从而揭示了个体发育中心肌细胞再生潜能丧失的潜在机制， 我是马根尼