Diversity Supplement Denzel Deo Omengan

项目摘要/摘要 大多数成年哺乳动物的组织和器官的再生潜力非常有限。有心脏的患者 发作时，心肌细胞的死亡和丢失是不可逆转的，通常会导致永久性的疤痕和 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迅速 让他们的心重新焕发活力。基因谱系追踪实验揭示了先前存在的 心肌细胞是产生新肌细胞的主要机制。然而，在出生后不久， 大多数哺乳动物的心肌细胞都经历了最后一轮DNA复制，没有 胞质分裂，变成双核，退出细胞周期。哪些生理信号会触发 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的 在具有不同心脏再生潜力的动物身上进行调控是最长期存在的问题之一 心肌细胞生物学。心肌细胞比较分析的初步观察 系统发育，体内候选途径的化学筛选，以及在小鼠和 斑马鱼提示围产期内分泌系统变化在驱动心肌细胞中的关键作用 哺乳动物心脏的增殖和再生潜能丧失。在这项提案中，我们计划将一个 利用最新的基因工具研究核功能的心肌细胞定量分析 激素受体激活在调节心肌细胞生后生长过程中的作用(目标1)和心脏 心肌损伤后再生(目标2)。此外，我们将研究托换蜂窝和 分子基础，确定新的下游靶基因在心肌细胞周期中的功能 通过增益法和损失法进行控制(目标3)。成功完成拟议的工作将 从而揭示了个体发育中心肌细胞再生潜力丧失的机制和 系统发育学。

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.