Uncoupling Protein Polymorphisms and Cardiometabolic Responses to Beta-Blockers

描述(由申请人提供)：这份K23申请旨在通过一个有组织的、有指导的计划来促进职业发展。该奖项将通过表征糖尿病患者中β-受体阻滞剂的心脏代谢反应的变异性，在心血管药物基因组学和功能基因组学领域发展专业知识。尽管在治疗心血管疾病(CVD)方面取得了许多进展，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。优化药物治疗对心血管疾病和2型糖尿病患者至关重要，因为这些患者1)经历特别激进的疾病过程，2)往往对传统的心血管疾病药物治疗产生抵抗，3)承受着不成比例的心血管疾病负担。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，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，药物基因组学提供了机会来表征药物反应中患者间变异性的遗传贡献。有丝分裂解偶联蛋白(UCPs)通过影响氧化应激、胰岛素敏感性和能量消耗，在心血管疾病、糖尿病和肥胖中发挥作用。在解释糖尿病患者与非糖尿病患者的预后差异时，编码UCPs的基因是高度优先的候选基因，可能与β-受体阻滞剂的有益机制有关，也可能与其对脂代谢的不利影响有关。本文提出的研究代表了一项在糖尿病患者中进行广泛表型的前瞻性药物遗传学研究，旨在为我们先前与UCP基因多态性和不利的β-受体阻滞剂结果之间的联系的机制和验证提供洞察力。在进行这项机械驱动的验证研究时，我们正在为将我们的发现转化为临床实践奠定框架。具体地说，该项目的目的是：1)使用灵敏的成像技术，比较UCP2-3基因型对β受体阻滞剂治疗的心脏功能的影响；2)确定携带UCP2-3基因的糖尿病患者对β受体阻滞剂治疗的24小时游离脂肪酸(FFA)动力学是否不同；以及3)评估UCP2-3基因多态性的功能后果，这可能是导致心血管药物反应不同的原因之一。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CV治疗的反应比其他患者更好，我们可能能够更恰当地治疗个别患者，从而改善结果。(摘要结束)

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)