Metabolic Effects of Antihypertensive Drugs

职业发展：这份K-23职业发展奖申请的目标是为候选人成为一名独立的以病人为导向的研究人员做好准备。申请人的主要兴趣领域是通过确定最大限度地提高胰岛素敏感性的药理和药物基因组组合来减轻与代谢综合征患者的抗高血压治疗相关的不良代谢影响。佛罗里达大学有资源为申请者提供理想的环境，在抗高血压治疗环境中检查胰岛素抵抗的临床和药物基因组学方面。拟议的职业发展计划纳入了以流行病学为重点的结构化教学计划，这将导致通过K30计划获得流行病学硕士学位。此外，申请者将参加由药物基因组学、流行病学和代谢综合征环境中的葡萄糖动态平衡领域的专家举办的研讨会、会议和以实验室为基础的重点研究教程。临床和实验室调查。以胰岛素抵抗为主要特征的代谢综合征患者患糖尿病的风险增加，并经常患有高血压(HTN)。尽管与导致胰岛素抵抗增加的代谢紊乱有关，噻嗪类利尿剂仍被推荐用于治疗代谢综合征患者的HTN。这项研究的主要假设是，在患有代谢综合征和HTN的患者中，用血管紧张素转换酶(ACE)抑制剂阻断肾素-血管紧张素系统(RAS)可以减轻噻嗪利尿剂的不良代谢影响。具体目的是调查在利尿剂中加入血管紧张素转换酶抑制剂后和/或在使用血管紧张素转换酶抑制剂的情况下是否会发生这种衰减。此外，还将在6000名高血压CAD患者中进行以实验室为基础的药物基因组研究，以确定ACE、ADD1和KCNJ1基因中与糖尿病相关的多态，这些基因是根据它们在ACE抑制物和利尿剂反应中的关键作用而选择的。这项研究试图克服有关代谢综合征患者抗高血压药物代谢影响的知识空白，并将为影响未来的处方模式提供数据。

DESCRIPTION (provided by applicant): Career Development: The objective of this K-23 Career Development Award application is to prepare the candidate for a career as an independent patient oriented researcher. The applicant's primary area of interest is in attenuating the adverse metabolic effects associated with antihypertensive therapy in patients with metabolic syndrome by identifying pharmacologic and pharmacogenomic combinations that maximize insulin sensitivity. The University of Florida has the resources to provide the applicant with the ideal setting to examine both the clinical and pharmacogenomic aspects of insulin resistance in the setting of antihypertensive therapy. The proposed career development plan incorporates a structured didactic program focused in epidemiology, which will result in a master's degree in epidemiology via the K30 program. Additionally, the applicant will participate in seminars, conferences and focused laboratory based research tutorials conducted by experts in the field of pharmacogenomics, epidemiology and glucose homeostasis in the setting of metabolic syndrome. Clinical and Laboratory Investigations. Patients with metabolic syndrome, characterized primarily by insulin resistance are at increased risk of developing diabetes and often have hypertension (HTN). Thiazide diuretics are recommended for treating HTN in patients with metabolic syndrome, despite being associated with metabolic disturbances that result in increased insulin resistance. The major hypothesis of this study is that in patients with metabolic syndrome and HTN, blockade of the renin-angiotensin system (RAS) with an angiotensin converting enzyme (ACE) inhibitor attenuates the adverse metabolic effects of a thiazide diuretic. Specific aims are designed to investigate whether this attenuation occurs after the addition of ACE inhibitor to diuretic and/or as a consequence of pretreatment with an ACE inhibitor. Also, laboratory based pharmacogenomic investigations will be conducted in a separate cohort of 6000 hypertensive CAD patients to identify polymorphisms associated with diabetes in the ACE, ADD1 and KCNJ1 genes, selected on the basis of their critical role in ACE inhibitor and diuretic response. This research seeks to overcome gaps in knowledge regarding the metabolic impact of antihypertensive drugs in patients with metabolic syndrome and will provide data to influence future prescribing patterns.