Retinoic Acid Signaling in Heart Development and Regeneration

描述（由申请人提供）：本提案概述了郭煌博士在Eric Olson博士的指导下完成进一步的学术培训并过渡到心脏发育和再生领域的独立研究者的综合培训和研究计划。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。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。心脏病是工业化国家发病率和死亡率的主要原因。心脏病发作时血液流动和氧气供应的中断通常会导致死亡和心肌细胞的损失，瘢痕形成和随后可能危及生命的心律失常。我们的心肌再生能力非常有限，如果有的话，这与成年斑马鱼和新生小鼠形成鲜明对比，它们可以再生高达15%的心脏。在这两种再生模型中，心肌细胞增殖被认为是主要的机制。在哺乳动物胚胎发育和成鱼心脏再生中，心外膜源性维甲酸（RA）及其下游信号通路在心肌细胞增殖和再生中都起着至关重要的作用。有趣的是，尽管RA合成途径在损伤后的成年小鼠心外膜中被重新激活，但心脏损伤后的下游RA反应似乎保持不活跃。了解RA信号在发病和损伤后的调控和功能，可能为我们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，目的1将描述限制酶RALDH2在胚胎心脏发育和缺血损伤后反应中对RA合成的转录调控。目的2将确定Raldh2在胚胎心脏发育和新生儿心脏再生中的功能。目的3将确定成年小鼠心外膜RA反应的增加是否能促进心脏损伤后的心脏再生。目的4将研究斑马鱼心脏再生过程中心外膜Raldh2调控和RA反应。在指导阶段，将完成目标1和目标2，并生成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进行研究。拟议的工作与NIH的使命密切相关，因为预期的结果将为心脏损伤激活的进化保守途径和成年哺乳动物心脏中差异调节的分子成分提供必要的见解，这可能解释了人类再生潜力的丧失。

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.