SYSTEMIC BRADYKININ IN HUMAN HYPERTENSION

候选人莱恩·默菲博士是一名获得董事会认证的内科医生和在心血管生理学研究方面经验丰富的药理学家。他寻求继续在高血压领域作为一名以患者为导向的研究人员，通过一项有指导的职业发展计划继续取得进步，该计划包括床边研究、实验室研究和生物统计学、遗传学和研究设计方面的重点课程。该项目将在范德比尔特大学进行，该大学对临床研究人员的指导性培训有着历史和坚定的承诺。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：缓激肽是一种保护心脏的多肽激素，是血管扩张剂和利钠药。在人类中，缓激肽有助于血管紧张素转换酶抑制剂的急性血流动力学效应，血管紧张素转换酶抑制剂是一种广泛使用的药物。研究表明，内源性缓激肽在人类高血压中可能减少，并受盐状态、种族和遗传因素的调节。到目前为止，人类对全身性缓激肽的研究一直被测量这种快速代谢的多肽的困难所困扰。以前的分析依赖于非特异性放射免疫分析技术。最近，我们对全身缓激肽在人体内的代谢进行了研究，确定BK1-5是缓激肽的主要稳定血浆代谢物。为了准确测定缓激肽和BK1-5，我们建立了针对这两种多肽的高特异性和高灵敏度的液质联用分析方法。总而言之，该领域的这些进展现在为确定全身性缓激肽在心血管内稳态中的作用提供了强有力的方法。在这个应用中，我建议使用这些新的工具来直接测试这一假设，即高血压患者全身性缓激肽降低，并且它受到遗传、种族和环境因素的调节。在有指导的环境中实施这些研究，再加上参与指导课程的工作，将为申请者提供成为一名独立的、以患者为中心的研究人员的工具。

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.