ENDOTHELIAL DYSFUNCTION IN HEART FAILURE

申请者的职业生涯表明他长期致力于以患者为导向的研究，在研究血管内皮细胞在心力衰竭患者外周血管舒缩张力调节中的作用方面拥有丰富的经验，并在指导研究员从事以患者为导向的研究方面有着良好的记录。哥伦比亚大学循环生理学分部承诺保护申请者50%的时间用于资助研究。申请者的研究工作进一步得到了医学部以及NIH和AHA正在进行的拨款的支持。这项以患者为中心的研究生涯中期奖将提供支持，以将正在进行的研究努力扩展到新的方向，并为年轻的临床研究人员创建一个全面的指导计划。这项研究计划的总体目标是描述心力衰竭时内皮功能障碍的病理生理学特征，以便为心力衰竭的治疗设计新的治疗策略。初步数据显示，可以通过测量血流介导的血管扩张(静脉阻塞体积图和多普勒超声)和测量一氧化氮合成(15N-L精氨酸稳定同位素示踪技术和呼气中一氧化氮的测量)来无创性地评估内皮功能，心力衰竭时的内皮功能障碍部分归因于血清中存在的一种可扩散因子，内皮功能障碍可能与氧化应激增加有关。我们现在建议1)鉴定心力衰竭患者内皮功能障碍的患病率、自然病史和预后意义；2)鉴定心力衰竭患者内皮细胞培养中存在的可扩散血清因子的影响；以及3)确定特定的抗氧化剂治疗是否可以逆转心力衰竭患者的内皮功能障碍。指导计划将由三个关键部分组成：1)面向患者研究的强化实践培训(参与本研究计划中描述的方案并创建独立研究项目)；2)哥伦比亚大学关于临床试验设计、临床研究中的数据分析、拨款申请和临床研究中的伦理问题的教学计划；3)哥伦比亚大学一个国际公认的以患者为导向的研究专家委员会对受训人员进展的持续审查。

The applicant's professional career demonstrates a long-term committment to patient-oriented research, extensive experience in the study of the role of the vascular endothelium in the regulation of peripheral vasomotor tone in patients with heart failure, and a strong record in mentoring fellows for careers in patient-oriented research. The Division of Circulatory Physiology at Columbia has committed to protect 50 percent of the applicant's time for grant-supported research. The applicant's research efforts are further supported by the Department of Medicine and ongoing NIH and AHA grants. This Midcareer Investigator Award in Patient-Oriented Research will provide support to expand ongoing research efforts into new directions and create a comprehensive mentoring program for young clinical investigators. The overall aim of this research proposal is to characterize the pathophysiology of endothelial dysfunction in heart failure in order to devise new therapeutic strategies for the treatment of heart failure. Preliminary data demonstrate that endothelial function can be assessed non-invasively by measurement of flow-mediated vasodilation (venous occlusion plethysmography and Doppler ultrasongography) and by measurement of nitric oxide synthesis (stable isotope tracer techniques with 15N-L-arginine and measurement of nitric oxide in exhaled gases), that endothelial dysfunction in heart failure is partly attributable to a diffusable factor present in the serum, and that endothelial dysfunction may be linked to increased oxidative stress. We now propose 1) to characterize the prevalence, natural history, and prognostic implications of endothelial dysfunction in heart failure; 2) to characterize the effects of the diffusable serum factor present in patients with heart failure in cultured endothelial cells; and 3) to determine whether specific antioxidant therapies can reverse endothelial dysfunction in patients with heart failure. The mentoring program will consist of three key components: 1) intensive practical training in patient-oriented research (participation in the protocols described in this research plan and creation of an independent research project); 2) Columbia University didactic programs on clinical trial design, data analysis in clinical research, grant writing, and ethical issues in clinical research; 3) ongoing review of trainee progress by a committee of internationally-recognized patient-oriented research experts at Columbia.