Vascular Dysfunction with Increased Pulmonary Blood Flow: A role for PPAR Gamma

描述(由申请人提供)： 这份提案描述了一项为期5年的培训计划，旨在发展转化性心血管研究的学术生涯。候选人，在完成儿科临床研究员学位后 重症监护医学和加州大学旧金山分校(UCSF)心血管研究所(CVRI)的研究奖学金现在准备充分发展维持独立研究计划所需的科学技能，利用CVRI和UCSF提供的著名的多学科环境。该培训计划旨在使应聘者能够应用综合的解剖学、生理学、生化、细胞和分子研究来解决与先天性心脏病相关的肺血管疾病的机制。发起人杰弗里·R·芬曼医学博士是加州大学旧金山分校的教授，也是国际公认的肺血管疾病专家，他有很强的成功指导历史。此外，一个由杰出医学科学家组成的咨询委员会将提供额外的科学支持和职业指导。实验技术、设计和分析方面的实践训练与辅助性教学课程工作相结合。这项拟议的研究计划试图阐明继发于肺血流增加的肺血管疾病的潜在机制，肺血流增加与几种先天性心脏病有关。芬曼博士实验室以前的工作表明，异常的一氧化氮(NO)和内皮素-1(ET-1)信号转导导致了这种病理。候选人随后产生了初步数据，这些数据表明PPARy在这些相互作用中发挥核心作用。利用独特的临床相关的先天性心脏病伴肺血流量增加的绵羊模型(在子宫内由主-肺移植物造成)，以及综合的生化、分子和细胞实验，该提案寻求实现以下目标：(1)确定在肺血流量增加的情况下内源性PPARy表达的变化，以及这些变化的机制和功能后果；(2)确定在肺血流量增加的情况下PPARy激动剂治疗引起的生理、生化、细胞和分子变化。PPARy在这种病理中的作用是新颖的。更好地了解这些相互作用可能对肺和全身血管疾病具有重要意义。 相关性：患有先天性心脏病伴肺血增多的婴儿和儿童 流、患肺血管疾病所致的发病率和死亡率。了解这种病理的控制机制可能会导致新的有效的预防和治疗策略，从而改善这一脆弱人群的生存和生活质量。 (摘要结束)

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in translational cardiovascular research. The candidate, having completed a clinical fellowship in Pediatric Critical Care Medicine, and a research fellowship at the Cardiovascular Research Institute (CVRI) at the University of California San Francisco (UCSF), is now poised to fully develop the scientific skill-set necessary to sustain an independent research program, utilizing the renowned, multidisciplinary environment offered by the CVRI and UCSF. The training program is designed to enable the candidate to apply integrated anatomic, physiologic, biochemical, cellular, and molecular investigations to addressing mechanisms of pulmonary vascular disease associated with congenital heart defects. The sponsor, Jeffrey R. Fineman, M.D., a Professor at UCSF and an internationally recognized expert in pulmonary vascular disease, has a strong history of successful mentorship. In addition, an advisory committee of distinguished medical scientists will provide additional scientific support and career guidance. Practical training in experimental techniques, design, and analysis Is combined with complementary didactic course-work. The proposed research plan seeks to elucidate the mechanisms underlying the development of pulmonary vascular disease secondary to increased pulmonary blood flow that is associated with several congenital heart defects. Previous work from Dr. Fineman's laboratory demonstrates that aberrant nitric oxide (NO) and endothelin-1 (ET-1) signaling contribute to this pathology. The candidate has subsequently generated preliminary data, which suggest a central role for PPARY in these interactions. Utilizing a unique clinically relevant ovine model of a congenital heart defect with increased pulmonary blood flow (created in utero by an aorto-pulmonary graft), and integrated biochemical, molecular, and cellular experiments, the proposal seeks to accomplish the following aims: (1) To determine alterations in endogenous PPARy expression under conditions of increased pulmonary blood flow, and the mechanisms and functional consequences of these alterations; and (2) To determine the physiologic, biochemical, cellular, and molecular alterations induced by PPARy agonist therapy under conditions of increased pulmonary blood flow. A role for PPARy in this pathology is novel. A better understanding of these interactions may have important implications for pulmonary as well as systemic vascular disorders. Relevance: Infants and children afflicted with congenital heart defects with increased pulmonary blood flow, suffer morbidity and mortality from the development of pulmonary vascular disease. Understanding the controlling mechanisms of this pathology might lead to novel and effective prevention and treatment strategies that will improve the survival and quality of life of this vulnerable population. (End of Abstract)