A Functional Role for Prolyl Hydroxylases (PHDs) in Cardiomyopathy

描述（由申请人提供）：本提案描述了一个为期4年的学术心血管（CV）医学职业发展培训计划。主要研究者已在布里格姆妇女医院完成了CV医学的临床和研究培训，并将开始一项研究计划，旨在提供独立生物医学研究职业所需的额外科学培训。该计划将为研究主转录因子缺氧诱导因子-a（HIFa）提供合理的原则和专业知识，因为它适用于肌细胞生物学和心力衰竭。霍华德休斯研究员、哈佛医学院医学教授、缺氧中细胞信号传导的先驱William Kaelin博士和哈佛医学院医学副教授、心肌细胞生物学专家Ronglin Liao博士之间的联合导师关系已经建立，以促进申请人的科学和职业发展。研究者已经在PHD 2缺陷的小鼠中建立了一种新型的自发性心力衰竭模型，PHD 2是一种调节HIF a稳定性和活性的脯氨酰羟化酶。该提议的具体目的是：1）确定体内和离体心肌细胞中PHD 2失活的功能后果。2)测试PHD 3是否部分补偿体内并且特别是心脏中的PHD 2损失3）测试HIF a对于心脏特异性PHD 2-/-小鼠中观察到的心肌病的发展是必要和充分的假设。相关性（参见说明）：心力衰竭是一个巨大的医疗和社会负担，影响着美国超过500万人，其发病率只会随着人口老龄化和心脏病患者寿命的延长而增加。这项研究旨在了解心力衰竭的基本机制，最终目标是找到预防和治疗这种毁灭性疾病的新疗法。 (End摘要）

DESCRIPTION (provided by applicant): This proposal describes a 4 year training program for career development in academic cardiovascular (CV) medicine. The principal investigator has completed clinical and research training in CV medicine at Brigham and Women's Hospital and will embark on a research program designed to provide additional scientific training required for an independent biomedical research career. This program will provide sound principles and expertise for studying the master transcription factor Hypoxia-Inducible Factor-a (HIFa) as it applies to myocyte biology and heart failure. A joint mentorship between Dr. William Kaelin, a Howard Hughes Investigator, Professor of Medicine at Harvard Medical School and a pioneer in cellular signaling in hypoxia, and Dr. Ronglin Liao, associate professor of medicine at Harvard Medical School and an expert in cardiomyocyte biology, has been forged to foster the applicant's scientific and career development. The investigator has established a novel model for spontaneous heart failure in mice deficient in PHD2, a prolyl hydroxylase that regulates the stabilization and activity of HIFa. The specific aims of this proposal are: 1) To determine the functional consequence of PHD2 inactivation in the cardiomycoyte in vivo and ex vivo. 2) To test whether PHD3 partially compensates for PHD2 loss in vivo and specifically in the heart 3) To test the hypothesis that HIFa is necessary and sufficient for the development of cardiomyopathy seen in cardiac- specific PHD2-/- mice. RELEVANCE (See instructions): Heart failure represents an enormous medical and societal burden, affecting over 5 million people in the USA, and its incidence is only increasing with an aging population and prolongation of the lives of cardiac patients. This research aims to understand the fundamental mechanisms of heart failure with the ultimate goal of finding new therapies to prevent and treat this devastating illness. (End of Abstract)