Retinoic Acid Signaling in Heart Development and Regeneration

项目摘要/摘要 这项建议勾勒出郭煌博士完成进一步学术研究的综合培训和研究计划 在埃里克·奥尔森博士的指导下接受培训，并过渡到专门研究 心脏发育和再生领域。该协会现为生命科学研究基金会会员 致力于小鼠和斑马鱼心脏损伤反应的比较研究。总的目标是 本研究的目的是了解维甲酸(RA)信号的调节机制和功能 在心脏发育和再生方面。心脏病发作是#年发病率和死亡率的主要原因。 工业化国家。心脏病发作期间血液流动和氧气供应的中断通常会导致 心肌细胞死亡和丢失、疤痕形成和随后潜在威胁生命的心脏 心律不齐。我们再生心肌的能力非常有限，如果有的话，这在很大程度上 相比之下，成年斑马鱼和新生小鼠的心脏可以再生高达15%。在这两种再生中 模型中，心肌细胞增殖被认为是主要机制。在两种哺乳动物的胚胎中 鱼的发育和成鱼心脏再生、心外膜衍生的维甲酸及其下游 信号通路在心肌细胞的增殖和再生中起着至关重要的作用。 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，但 心脏损伤后的下游RA反应似乎仍处于不活跃状态。了解法规和 RA信号在发育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进展。在研究计划中，目标1将描绘 胚胎心脏RA合成限速酶RALDH2的转录调控 发展和缺血后的损伤反应。目标2将定义Raldh2在胚胎心脏中的功能 发育与新生儿心脏再生。目标3将确定成人的类风湿反应是否获得 小鼠心外膜可促进心脏损伤后的心脏再生。目标4将研究斑马鱼Raldh2 斑马鱼心脏再生过程中心外膜的调节和RA反应。在指导阶段， 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。拟议的工作是密切相关的 与NIH的任务相关，因为预期的结果将提供关于进化的基本见解 心脏损伤激活的保守通路和差异调控的分子成分 成年哺乳动物的心脏，可能解释了人类再生能力的丧失。

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.