A Functional Role for Prolyl Hydroxylases (PHDs) in Cardiomyopathy

描述(由申请人提供)：本建议书描述了一项为期4年的心血管(CV)学术医学职业发展培训计划。首席研究员已在布里格姆妇女医院完成了心血管医学的临床和研究培训，并将开始一项旨在提供独立生物医学研究生涯所需的额外科学培训的研究计划。该项目将为研究主要转录因子缺氧诱导因子-a(HIFA)提供可靠的原理和专业知识，因为它应用于心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、低氧细胞信号传导先驱威廉·凯林博士与哈佛医学院医学副教授、心肌生物学专家廖荣林博士结成了联合导师关系，以促进申请者的科学和职业发展。这位研究人员在缺乏PHD2的小鼠中建立了一种新的自发性心力衰竭模型。PHD2是一种调节HIFA稳定性和活性的Pro羟基酶。这项建议的具体目的是：1)确定PHD2失活在体内和体外心肌细胞中的功能后果。2)测试PHD3是否能部分补偿体内特别是心脏中PHD2的丢失；3)测试HIFA对于心脏特异的PHD2-/-小鼠心肌病的发生是必要的和充分的这一假设。相关性(参见说明)：心力衰竭是一个巨大的医疗和社会负担，在美国影响着500多万人，而且随着人口老龄化和心脏病患者寿命的延长，其发病率只会增加。这项研究旨在了解心力衰竭的基本机制，最终目的是找到预防和治疗这种毁灭性疾病的新疗法。(摘要结束)

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)