Retinoic Acid Signaling in Heart Development and Regeneration

心脏发育和再生中的视黄酸信号传导

• 批准号: 8523967
• 负责人: Guo Huang
• 金额: $ 12.46万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2013-12-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8523967
• 关键词: Academic Training; Accounting; Address; Adult; Arrhythmia; Biological Assay; Biological Sciences; Blood flow; CCAAT-Enhancer-Binding Proteins; Cardiac; Cardiac Myocytes; Cells; Cessation of life; Cicatrix; Comparative Study; Data; Defect; Developed Countries; Development; Dominant-Negative Mutation; Embryo; Embryonic Development; Embryonic Heart; Embryonic Ventricle; Encapsulated; Enhancers; Enzymes; Epicardium; Epithelial Cells; Exhibits; Family; Family member; Fishes; Foundations; Future; Genetic Models; Heart; Heart Injuries; Human; Injury; Interruption; Investigation; Knockout Mice; Life; Mentors; Mentorship; Mission; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Neonatal; Organ; Organogenesis; Outcome; Oxygen; Pathway interactions; Patients; Phase; Process; Publishing; Recovery; Regulation; Reporter; Reporting; Research; Research Personnel; Research Proposals; Research Training; Retinoic Acid Receptor; Role; Sequence Homologs; Signal Pathway; Signal Transduction; Staging; Testing; Tissues; Transcriptional Regulation; Transfection; Transgenic Model; Transgenic Organisms; Tretinoin; VP 16; Work; Zebrafish; base; cardiogenesis; drug development; in vivo; injured; insight; mortality; new therapeutic target; novel; regenerative; response; response to injury; transcription factor; virus genetics

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.

描述（由申请人提供）：本提案概述了黄果博士的综合培训和研究计划，以在埃里克·奥尔森博士的指导下完成进一步的学术培训，并过渡为专门从事心脏发育和再生领域的独立研究者。 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视黄酸（RA）信号在心脏发育和再生中的调节机制和功能。心脏病发作是工业化国家发病和死亡的主要原因。心脏病发作期间血流和氧气供应中断通常会导致心肌细胞死亡和损失、疤痕形成以及随后可能危及生命的心律失常。我们的心肌再生能力（如果有的话）非常有限，这与成年斑马鱼和新生小鼠的心脏再生能力高达 15% 形成鲜明对比。在这两种再生模型中，心肌细胞增殖被认为是主要机制。在哺乳动物胚胎发育和成鱼心脏再生中，心外膜衍生的视黄酸（RA）及其下游信号通路对于心肌细胞增殖和再生至关重要。有趣的是，尽管成年小鼠心外膜损伤后 RA 合成途径重新激活，但心脏损伤后下游 RA 反应似乎仍然不活跃。了解发育过程中和损伤后 RA 信号传导的调节和功能可能为我们提供药物开发的新治疗靶点，以促进心脏病发作后的心肌细胞再生。在该研究计划中，目标1将描述胚胎心脏发育和缺血后损伤反应过程中RA合成的限速酶RALDH2的转录调控。目标 2 将定义 Raldh2 在胚胎心脏发育和新生儿心脏再生中的功能。目标 3 将确定成年小鼠心外膜中 RA 反应的增强是否可以促进心脏损伤后的心脏再生。目标 4 将研究斑马鱼心脏再生过程中心外膜中 Raldh2 的调节和 RA 反应。在指导阶段，将完成目标1和目标2，并将生成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。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重要的见解，这可能是人类再生潜力丧失的原因。 。