Genetic Mechanisms of Cardiac Adaptation To Hypoxia

心脏适应缺氧的遗传机制

• 批准号: 8001449
• 负责人: ROLF BODMER
• 金额: $ 51.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8001449
• 关键词: Ablation; Acute; Affect; Alleles; Animals; Bioinformatics; Biological Assay; Blood Vessels; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Chronic; Coronary; Data; Drosophila genus; Ensure; Epicardium; Evolution; Exposure to; Genes; Genetic; Genetic Enhancer Element; Goals; Heart; Heart Hypertrophy; Heart Rate; Human; Human Resources; Hypoxia; Infarction; Injury; Insulin; Knowledge; Lead; Lung; Magnetic Resonance Imaging; Measures; Mediating; Modeling; Molecular; Mus; Mutation; Myocardial; Myocardial Infarction; Myocardium; Organ; Outcome; Oxygen; Pathway interactions; Pericardial body location; Physiological; Physiology; Predisposition; Protocols documentation; Pulmonary Hypertension; Regulation; Role; Signal Transduction; Stem cells; Stress; System; Systems Biology; Testing; Tissues; Transgenic Organisms; base; biological adaptation to stress; constriction; data sharing; fly; gain of function; heart function; hemodynamics; improved; in vivo; insight; mutant; myocardial hypoxia; notch protein; progenitor; programs; protective effect; reconstruction; research study; response; restoration

The Notch pathway, as well as potential regulators or effectors HIFa/Notch signaling, have emerged as particulariy relevant for establishing and maintaining heart funcfion under hypoxic stress conditions. We generated/collected mutafions of HIFa and Notch signaling in mulfiple cardiac compartments. We have gathered data suggesfing that genefic ablation of Notch pathway acfivity in the mouse myocardium does not lead to cardiac remodeling in response to hypoxic condifions caused by myocardial infarcfion, but rather has a protective effect on cardiomyocytes after the infarct. Moreover, in the Drosophila heart model, an acute response to hypoxia (slowing of the heart rate) does not occur when Notch signaling is acfivated in the heart, and chronic hypoxia leads to a non-contracfile, infarct-like condition of the heart. In contrast, HIF/Notch mutafions in the mouse epicardium are deleterious to heart funcfion, in that the response to transaortic constricfion is aggravated and cardiac hypertrophy is increased. Thus, the epicardium plays also a crifical role in the cardiac response to hypoxia. Thus, modulafion of HIF as well as Notch signaling in various cardiac compartments is crifical for the heart to respond and tolerate hypoxic conditions. We hypothesize that the interaction between HIF and Notch pathways are key to the regulafion of the response to hypoxia, that HIF/Notch signaling elicits unique responses in the myocardium versus the epicardium, and that the HIF/Notch-dependent mechanisms protect cardiac function. In this proposal, we will study the respective contribution and interacfions of HIF and Notch signaling to hypoxia tolerance and susceptibility in the heart. Based on the evolufionary conservafion of the hypoxia response, mechanisms of cardiac hypoxia responses identified in the fly heart, involving HIF and Notch signaling, promise to be of relevance to the mammalian heart. Insights gained here are likely to lead to new avenues for finding treatments for hypoxia-induced cardiac injury.

Notch 通路以及潜在的调节器或效应器 HIFa/Notch 信号传导已成为 尤其与缺氧应激条件下建立和维持心脏功能相关。我们 在多个心脏室中生成/收集 HIFa 和 Notch 信号传导的突变。我们有 收集的数据表明，小鼠心肌中 Notch 通路活性的基因消融并不 导致心脏重塑以应对心肌梗塞引起的缺氧条件，而是 对梗塞后心肌细胞有保护作用。此外，在果蝇心脏模型中，急性 当Notch信号在大脑中被激活时，不会发生对缺氧的反应（心率减慢） 心脏，慢性缺氧会导致心脏出现非收缩性、梗塞样状况。相比之下， 小鼠心外膜中的 HIF/Notch 突变对心脏功能有害，因为对 经主动脉缩窄加剧，心脏肥厚增加。因此，心外膜也起着 在心脏对缺氧的反应中起关键作用。因此，HIF 和 Notch 信号传导的调节 不同的心脏室对于心脏的反应和耐受缺氧条件至关重要。我们 假设 HIF 和 Notch 通路之间的相互作用是反应调节的关键 对于缺氧，HIF/Notch 信号传导在心肌中与心外膜中引发独特的反应，并且 HIF/Notch 依赖性机制可保护心脏功能。在本提案中，我们将研究 HIF 和 Notch 信号对缺氧耐受性和易感性的各自贡献和相互作用 心脏。基于缺氧反应的进化保守性，心脏缺氧的机制 在果蝇心脏中发现的反应，涉及 HIF 和 Notch 信号传导，有望与 哺乳动物的心脏。这里获得的见解可能会为寻找治疗方法开辟新途径 缺氧引起的心脏损伤。