ENDOTHELIAL DYSFUNCTION IN HEART FAILURE

申请人的职业生涯表明了对以患者为导向的研究的长期承诺，在心力衰竭患者外周血管张力调节中血管内皮作用的研究方面的丰富经验，以及在指导研究员从事以患者为导向的研究方面的良好记录。 哥伦比亚大学循环生理学系承诺保护申请人50%的时间用于资助研究。 申请人的研究工作得到了医学部和正在进行的NIH和AHA赠款的进一步支持。 这项以患者为导向的研究中期研究者奖将为将正在进行的研究工作扩展到新的方向提供支持，并为年轻的临床研究者创建一个全面的指导计划。 本研究的总体目标是描述心力衰竭中内皮功能障碍的病理生理学特征，以设计治疗心力衰竭的新治疗策略。 初步数据表明，内皮功能可以评估非侵入性的测量流量介导的血管舒张（静脉闭塞体积描记术和多普勒超声描记术）和通过测量一氧化氮合成（用15 N-L-精氨酸的稳定同位素示踪技术和呼出气体中一氧化氮的测量），心力衰竭中的内皮功能障碍部分归因于血清中存在的扩散因子，并且内皮功能障碍可能与氧化应激增加有关。 我们现在建议：1）描述心力衰竭患者内皮功能障碍的患病率、自然史和预后意义; 2）描述心力衰竭患者中存在的弥散性血清因子对培养的内皮细胞的影响; 3）确定特异性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。 指导计划将包括三个关键组成部分：1）在以患者为导向的研究中进行密集的实践培训（参与本研究计划中描述的方案并创建独立的研究项目）; 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、赠款撰写和临床研究中的伦理问题的教学计划; 3）由哥伦比亚国际公认的以患者为导向的研究专家委员会对受训者的进展进行持续审查。

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.