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）：该提案概述了Guo Huang博士的综合培训和研究计划，旨在在Eric Olson博士的指导下完成进一步的学术培训，并过渡到专门研究心脏发展和再生领域的独立研究人员。 PI目前是一名生命科学研究基金会，研究了小鼠和斑马鱼中心脏损伤反应的比较研究。研究建议的总体目的是了解视黄酸（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率的主要原因。心脏病发作过程中血流和氧气供应的中断通常会导致死亡和心肌细胞的丧失，疤痕形成以及随后可能威胁生命的心律不齐。我们的再生能力非常有限，可以再生心脏肌肉，这与成年斑马鱼和新生儿小鼠形成鲜明对比，后者可以再生多达15％的心脏。在这两个再生模型中，心肌细胞增殖都被认为是主要的机制。在哺乳动物的胚胎发育和成年鱼心脏再生中，心外膜衍生的视黄酸（RA）及其下游信号通路被牵涉到心肌细胞增殖和再生中必不可少的。有趣的是，尽管RA合成途径在损伤后在成年小鼠心外膜中重新激活，但下游RA反应后心脏损伤似乎仍然不活跃。了解在发育期间和受伤后RA信号的调节和功能可能为我们提供新颖的药物开发治疗靶标，以促进心脏病发作后促进心肌细胞再生。在研究计划中，AIM 1将描述限制速率酶RALDH2在胚胎心脏发育和缺血后损伤反应过程中的转录调节。 AIM 2将定义RALDH2在胚胎心脏发育和新生儿心脏再生中的功能。 AIM 3将确定成年小鼠心外膜中RA反应的增益是否可以在心脏损伤后促进心脏再生。 AIM 4将研究斑马鱼心脏再生期间心外膜中的斑马鱼Raldh2调节和RA反应。在指导阶段，AIM 1和AIM 2将完成，将生成新的鼠标和斑马鱼转基因模型，以持续调查AIM 3和AIM 4在独立阶段。拟议的工作与NIH的使命密切相关，因为预期的结果将为成年哺乳动物心脏中受差异调节的心脏损伤和分子成分激活的进化保守途径提供基本见解，这些途径可能解释了人类再生潜力的丧失。