SYSTEMIC BRADYKININ IN HUMAN HYPERTENSION

候选人Laine Murphey博士是一名委员会认证的内科医生和药理学家，在心血管生理学研究方面经验丰富。他寻求通过指导的职业发展计划，包括床边研究，实验室研究和生物统计学，遗传学和研究设计的重点课程，继续发展为高血压领域以患者为导向的独立研究人员。该计划将在范德比尔特大学进行，该大学对临床研究人员的指导培训有着历史性的坚定承诺。范德比尔特的综合临床研究中心为拟议的人体研究提供了理想的环境。研究：缓激肽，一种心脏保护肽激素，是一种血管扩张剂和利尿钠。在人类中，缓激肽有助于ACE抑制剂的急性血液动力学效应，ACE抑制剂是一类广泛使用的药物。研究表明，内源性缓激肽可能在人类高血压中减少，并且受盐状态、种族和遗传因素的调节。迄今为止，人体研究的全身性缓激肽已混淆的困难，在测量这种快速代谢的肽。先前的测定依赖于非特异性放射免疫测定技术。最近，我们研究了全身性缓激肽的人体内代谢，并鉴定出BK 1 - 5为缓激肽的主要稳定血浆代谢物。为了准确地测量缓激肽和BK 1 -5，我们已经开发了这两种肽的高度特异性和灵敏度的液相色谱-质谱分析。总之，该领域的这些进展现在提供了强有力的方法来确定系统性缓激肽在心血管稳态中的作用。在这个应用程序中，我建议使用这些新的工具来直接测试的假设，即系统性缓激肽降低高血压，它是由遗传，种族和环境因素调制。这些研究在指导环境中的实施，以及参与指导课程工作，将为申请人提供成为独立的以患者为导向的研究人员的工具。

The candidate, Dr. Laine Murphey, is a board certified internist and a pharmacologist experienced in studies of cardiovascular physiology. He seeks to continue to progress to independence as a patient-oriented researcher in the field of hypertension through a mentored career development plan that includes bedside research, laboratory studies and a focused curriculum in biostatistics, genetics and study design. The program will take place at Vanderbilt University, which has an historic and strong commitment to the mentored training of clinical researchers. The General Clinical Research Center at Vanderbilt provides the ideal environment for the proposed human studies. Research: Bradykinin, a cardioprotective peptide hormone, is a vasodilator and a natriuretic. In humans, bradykinin contributes to the acute hemodynamic effects of ACE inhibitors, a widely used class of drugs. Studies suggest that endogenous bradykinin may be decreased in human hypertension and that it is modulated by salt-status, ethnic and genetic factors. To date, human studies of systemic bradykinin have been confounded by difficulties in measuring this rapidly metabolized peptide. Prior assays have relied on non-specific radioimmunoassay techniques. Recently, we studied the human in vivo metabolism of systemic bradykinin and identified BK1 -5 as the major stable plasma metabolite of bradykinin. To accurately measure bradykinin and BK1-5, we have developed highly specific and sensitive liquid chromatography-mass spectroscopy assays for these two peptides. Together, these advances in the field now provide powerful methods to determine the role of systemic bradykinin in cardiovascular homeostasis. In this application, I propose to use these new tools to test directly the hypothesis that systemic bradykinin is decreased in hypertension and that it is modulated by genetic, ethnic and environmental factors. The implementation of these studies in a mentored environment, together with participation in directed course work, will provide the applicant with the tools to become an independent patient-oriented researcher.