Uncoupling Protein Polymorphisms and Cardiometabolic Responses to Beta-Blockers

描述（由申请人提供）：这个K23申请旨在通过一个结构化的、有指导的项目来促进职业发展。该奖项将允许心血管药物基因组学和功能基因组学领域的专业知识的发展，通过表征β受体阻滞剂在糖尿病患者中心脏代谢反应的可变性。尽管在心血管疾病的治疗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CVD和2型糖尿病患者的药物治疗是至关重要的，因为这些患者1)经历一个特别具有侵袭性的疾病过程，2)通常对传统的CVD药物治疗产生耐药性，3)承受着不成比例的CVD负担。导致糖尿病患者预后不良的因素在很大程度上仍然未知。一些常用的心血管药物，如-受体阻滞剂，具有不良的代谢特征，其机制尚不完全清楚，这可能会降低其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药物益处的衰减，药物基因组学提供了表征药物反应中患者间差异的遗传贡献的机会。线粒体解偶联蛋白（UCPs）通过对氧化应激、胰岛素敏感性和能量消耗的影响，被认为在心血管疾病、糖尿病和肥胖中发挥作用。编码ucp的基因是解释糖尿病患者与非糖尿病患者预后差异的优先候选基因，可能有助于β受体阻滞剂的有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UCP多态性和不良β受体阻滞剂结果之间的机制和验证。在进行这项机械驱动的验证研究时，我们正在为将我们的发现转化为临床实践奠定框架。具体来说，该项目旨在：1)利用UCP2-3基因型的敏感成像技术比较β受体阻滞剂治疗对心功能的影响；2)确定β受体阻滞剂治疗对24小时游离脂肪酸（FFA）动力学的反应在UCP2-3基因型的糖尿病患者中是否存在差异；3)评估UCP2-3基因型多态性的功能后果，这可能导致对CV药物的反应差异。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死亡的主要原因。通过更好地理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，我们可能能够更恰当地治疗个体患者，从而改善预后。（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)