Uncoupling Protein Polymorphisms and Cardiometabolic Responses to Beta-Blockers

描述（由申请人提供）：此 K23 申请旨在通过结构化的指导计划促进职业发展。该奖项将通过表征糖尿病患者中β受体阻滞剂心脏代谢反应的变异性，促进心血管药物基因组学和功能基因组学领域专业知识的发展。尽管心血管疾病（CVD）的治疗取得了许多进展，但发病率和死亡率仍然高得令人无法接受，特别是在糖尿病患者中。药物治疗的优化对于 CVD 和 2 型糖尿病患者至关重要，因为这些患者 1) 经历特别侵袭性的疾病过程，2) 通常对传统的 CVD 药物疗法有抵抗力，3) 承受不成比例的 CVD 负担。导致糖尿病患者预后不良的因素在很大程度上仍不清楚。一些常用的心血管药物（例如β受体阻滞剂）具有不良代谢特征，其机制尚不完全清楚，这可能会削弱它们预防某些患者不良后果的能力。重要的是要确定哪些患者可能会经历这种药物益处的减弱，而药物基因组学提供了描述遗传因素对患者间药物反应变异性的影响的机会。线粒体解偶联蛋白 (UCP) 通过影响氧化应激、胰岛素敏感性和能量消耗而在 CVD、糖尿病和肥胖症中发挥作用。编码 UCP 的基因作为候选基因在解释糖尿病患者与非糖尿病患者的结局差异方面具有高度优先性，并且可能有助于 β 受体阻滞剂的获益机制或其对脂质代谢的不利影响。本文提出的研究代表了一项前瞻性药物遗传学研究，在糖尿病患者中进行了广泛的表型分析，旨在深入了解我们之前与 UCP 多态性和不良 β 受体阻滞剂结果之间的关联的机制和验证。在进行这项机械驱动的验证研究时，我们正在奠定将我们的研究结果转化为临床实践的框架。具体而言，该项目旨在：1) 使用敏感成像技术根据 UCP2-3 基因型比较对 β 受体阻滞剂治疗的心脏功能，2) 确定不同 UCP2-3 基因型的糖尿病患者对 β 受体阻滞剂治疗的 24 小时游离脂肪酸 (FFA) 动力学是否存在差异，以及 3) 评估 UCP2-3 多态性的功能后果，这可能导致对 CV 药物反应的差异。这项研究具有重要的公共卫生意义，因为心血管疾病是糖尿病患者死亡的主要原因。通过更好地了解为什么一些糖尿病患者对心血管疗法的反应比其他患者更有利，我们也许能够更适当地治疗个别患者，从而改善预后。 （摘要完）

DESCRIPTION (provided by applicant): This K23 application is aimed at promoting career development through a structured, mentored program. This award will allow the development of expertise in the area of cardiovascular pharmacogenomics and functional genomics by characterizing variability in the cardiometabolic responses of beta-blockers among individuals with diabetes. Despite numerous advances made in the treatment of cardiovascular disease (CVD), morbidity and mortality remain unacceptably high, particularly among people with diabetes. The optimization of drug therapy is critical in patients with CVD and type 2 diabetes, as these patients 1) experience a particularly aggressive disease process, 2) are often resistant to traditional CVD pharmacotherapies, and 3) bear a disproportionate burden of CVD. The factors contributing to poor outcomes experienced by diabetic individuals remain largely unknown. Some commonly prescribed CV medications, such as beta-blockers, have adverse metabolic profiles, the mechanisms of which are not completely understood, that may dampen their ability to prevent adverse outcomes in some patients. It is important to identify which patients may experience this attenuation of drug benefit, and pharmacogenomics provides the opportunity to characterize the genetic contribution to inter-patient variability in drug responses. The mitochpndrial uncoupling proteins (UCPs) have been suggested to play a role in CVD, diabetes, and obesity through their effects on oxidative stress, insulin sensitivity, and energy expenditure. The genes that encode the UCPs are of high priority as candidate genes in explaining the discrepancy in outcomes experienced by diabetic patients compared to non-diabetic patients and may contribute to beta-blockers' mechanism of benefit or to their adverse effects on lipid metabolism. The studies proposed herein represent a prospective pharmacogenetic study with extensive phenotyping in diabetic patients designed to provide insight into the mechanism and validation of our previous association with UCP polymorphisms and adverse beta-blocker outcomes. In doing this mechanistically-driven validation study, we are laying the framework for translating our findings into clinical practice. Specifically, this project aims to: 1) compare cardiac function in response to beta-blocker treatment using sensitive imaging techniques by UCP2-3 genotypes, 2) determine whether 24-hour free fatty acid (FFA) kinetics in response to beta-blocker therapy differ among individuals with diabetes by UCP2-3 genotypes, and 3) evaluate the functional consequences of UCP2-3 polymorphisms which may contribute to differences in response to CV medications. This study has important public health implications in that CVD is the leading cause of death in diabetes. By better understanding why some patients with diabetes respond more favorably to CV therapies than others, we may be able to more appropriately treat individual patients, thereby improving outcomes. (End of Abstract)