Retinoic Acid Signaling in Heart Development and Regeneration

描述(申请人提供)：本建议书概述了郭黄博士的综合培训和研究计划，以便在Eric Olson博士的指导下完成进一步的学术培训，并过渡到专门从事心脏发育和再生领域的独立研究员。PI目前是生命科学研究基金会的研究员，致力于小鼠和斑马鱼心脏损伤反应的比较研究。该研究计划的总体目标是了解维甲酸(RA)信号在心脏发育和再生中的调节机制和功能。在工业化国家，心脏病发作是发病率和死亡率的主要原因。心脏病发作期间血流和氧气供应的中断通常会导致心肌细胞死亡和丧失，疤痕形成，以及随后可能危及生命的心律失常。我们再生心肌的能力非常有限，如果有的话，这与成年斑马鱼和新生小鼠形成鲜明对比，后者可以再生高达15%的心脏。在这两种再生模式中，心肌细胞增殖被认为是主要机制。在哺乳动物胚胎发育和成年鱼心脏再生中，心外膜衍生的维甲酸(RA)及其下游信号通路在心肌细胞的增殖和再生中都是必不可少的。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，但心脏损伤后下游的RA反应似乎仍然不活跃。了解RA信号在发育过程中和损伤后的调节和功能，可能为开发促进心肌细胞再生的药物提供新的治疗靶点。在研究计划中，Aim 1将描述限速酶RALDH2在胚胎心脏发育和缺血后损伤反应中合成RA的转录调控。目的2明确Raldh2在胚胎心脏发育和新生儿心脏再生中的作用。目的3确定成年小鼠心外膜RA反应增强是否能促进心脏损伤后的心脏再生。目的4研究斑马鱼心脏再生过程中心外膜Raldh2的调节和RA反应。在指导阶段，将完成目标1和目标2，并将产生新的小鼠和斑马鱼转基因模型，以便在独立阶段继续研究目标3和目标4。这项拟议的工作与NIH的任务密切相关，因为预期的结果将为心脏损伤激活的进化保守通路以及成年哺乳动物心脏中可能导致人类再生潜力丧失的不同调控的分子成分提供重要的见解。

DESCRIPTION (provided by applicant): 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.