Retinoic Acid Signaling in Heart Development and Regeneration

项目总结/摘要 本建议书概述了郭煌博士完成进一步学术研究的综合培训和研究计划 在Eric Olson博士的指导下接受培训，并过渡到一名独立的调查员，专门从事 心脏发育和再生领域。PI目前是生命科学研究基金会研究员 致力于小鼠和斑马鱼心脏损伤反应的比较研究。的总体目标 本研究的目的是了解维甲酸（RA）信号通路的调控机制和功能 心脏的发育和再生心脏病发作是发病和死亡的主要原因， 工业化国家。心脏病发作时血流和氧气供应的中断通常会导致 心肌细胞死亡和损失、瘢痕形成以及随后可能危及生命的心脏病 心律不齐我们有非常有限的再生能力，如果有的话，再生心肌，这是在伟大的 而成年斑马鱼和新生小鼠的心脏再生率高达15%。在这两个再生 模型中，心肌细胞增殖被认为是主要机制。在哺乳动物胚胎中， 发育和成鱼心脏再生，心外膜衍生的视黄酸（RA）及其下游 信号传导途径在心肌细胞增殖和再生中是必需的。 有趣的是，尽管成年小鼠心外膜损伤后RA合成途径被重新激活， 心脏损伤后的下游RA反应似乎保持不活跃。了解法规和 RA信号在发育过程中和损伤后的作用可能为我们提供新的药物治疗靶点 心脏病发作后促进心肌细胞再生的研究。在研究计划中，目标1将描述 胚胎心脏RA合成限速酶RALDH 2的转录调控 发展和缺血后损伤反应。目的2明确Raldh 2在胚胎心脏中的功能 发育和新生儿心脏再生。目的3将确定成人RA反应的获得是否 小鼠心外膜可促进心脏损伤后的心脏再生。Aim 4将研究斑马鱼Raldh 2 斑马鱼心脏再生过程中心外膜的调节和RA反应。在辅导阶段， 目标1和目标2将完成，并将产生新的小鼠和斑马鱼转基因模型， 在独立阶段继续对目标3和目标4进行调查。拟议的工作密切 与NIH的使命相关，因为预期的结果将提供关于进化的重要见解。 由心脏损伤激活的保守途径和在心脏损伤中差异调节的分子组分， 成年哺乳动物的心脏可能是人类失去再生能力的原因。

Project Summary/Abstract This proposal outlines an integrated training and research plan for Dr. Guo Huang to complete further academic training under the mentorship of Dr. Eric Olson and transition to an independent investigator specializing in the field of heart development and regeneration. The PI is currently a Life Sciences Research Foundation Fellow working on comparative studies of the cardiac injury response in mouse and zebrafish. The overall objective of the research proposal is to understand the regulatory mechanisms and functions of retinoic acid (RA) signaling in heart development and regeneration. Heart attacks are the leading cause of morbidity and mortality in industrialized countries. An interruption of blood flow and oxygen supply during a heart attack often leads to death and loss of heart muscle cells, scar formation and subsequent potentially life-threatening cardiac arrhythmias. We have very limited, if any, regeneration ability to regrow cardiac muscles, which is in great contrast with adult zebrafish and neonatal mice that can regenerate up to 15% of the heart. In both regeneration models, cardiomyocyte proliferation is believed to be the dominant mechanism. In both mammalian embryonic development and adult fish heart regeneration, the epicardium-derived retinoic acid (RA) and its downstream signaling pathways have been implicated to be essential in cardiomyocyte proliferation and regeneration. Intriguingly, although the RA synthesis pathway is reactivated in the adult mouse epicardium after injury, the downstream RA response post-cardiac injury seems to remain inactive. Understanding the regulation and function of RA signaling during development and after injury might provide us novel therapeutic targets for drug development to promote myocyte regeneration following heart attacks. In the research plan, aim 1 will delineate the transcriptional regulation of the rate-limiting enzyme RALDH2 for RA synthesis during embryonic heart development and post-ischemic injury responses. Aim 2 will define the function of Raldh2 in embryonic heart development and neonatal heart regeneration. Aim 3 will determine whether gain of RA responses in the adult mouse epicardium can promote heart regeneration after cardiac injury. Aim 4 will study zebrafish Raldh2 regulation and RA response in the epicardium during zebrafish heart regeneration. In the mentored phase, the aim 1 and aim 2 will be completed, and new mouse and zebrafish transgenic models will be generated for continued investigation towards aim 3 and aim 4 in the independent phase. The proposed work is closely relevant to NIH's mission in that the expected outcome will provide essential insights on the evolutionarily conserved pathways activated by cardiac injury and molecular components that are differentially regulated in the adult mammalian heart that may account for the loss of regeneration potential in human.