Uncoupling Protein Polymorphisms and Cardiometabolic Responses to Beta-Blockers

解偶联蛋白质多态性和对 β 受体阻滞剂的心脏代谢反应

基本信息

批准号：
8309473
负责人：
AMBER L BEITELSHEES
金额：
$ 13.28万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309473
关键词：
Adrenergic beta-Antagonists Adverse effects Alleles Amber Animals Area Award Binding Candidate Disease Gene Cardiac Cardiovascular Diseases Cardiovascular system Cause of Death Clinical Cyclic AMP Response Element Cyclic AMP-Responsive DNA-Binding Protein Development Development Plans Diabetes Mellitus Disease Energy Metabolism Equilibrium Event Florida Gene Cluster Genes Genetic Genetic Polymorphism Genotype Glucose Heart Hour Imaging Techniques In Vitro Individual Kinetics Lipids Lipolysis Mentors Messenger RNA Metabolic Mitochondria Morbidity - disease rate Myocardial Myocardial dysfunction Myocardial perfusion Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Outcome Oxidative Stress Patients Peripheral Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacotherapy Phenotype Play Process Proteins Public Health Relative (related person)Research Research Personnel Resistance Risk Role Scientist Single Nucleotide Polymorphism Site Skeletal Muscle Structure Technetium 99m Translating Translational Research Universities Ursidae Family Validation Variant abstracting acute coronary syndrome adverse outcome attenuation career development clinical practice cohort design diabetic diabetic patient experience fatty acid metabolism fatty acid oxidation functional genomics improved insight insulin sensitivity lipid metabolism metabolic abnormality assessment mortality non-diabetic prevent programs promoter prospective protein expression response single photon emission computed tomography skills validation studies

项目摘要

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)

描述（由申请人提供）：此K23申请旨在通过结构化的指导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可变性来发展心血管药物基因组学和功能基因组学领域的专业知识。尽管在治疗心血管疾病（CVD）方面取得了许多进步，但发病率和死亡率仍然令人难以置信，尤其是在糖尿病患者中。在CVD和2型糖尿病患者中，药物治疗的优化至关重要，因为这些患者1）经历特别侵略性的疾病过程，2）通常对传统的CVD药物治疗具有抵抗力，而3）承担CVD的不成比例。导致糖尿病患者经历的不良结果的因素在很大程度上尚不清楚。一些常规开处方的CV药物（例如β受体阻滞剂）具有不良代谢谱，其机制尚未完全了解，这可能会抑制它们防止某些患者不良结果的能力。重要的是要确定哪些患者可能会遭受这种药物益处的衰减，而药物基因组学为表征对药物反应的患病率变异性的遗传贡献提供了机会。已经建议通过对氧化应激，胰岛素敏感性和能量消耗的作用来在CVD，糖尿病和肥胖症中发挥作用。与非糖尿病患者相比，在解释糖尿病患者所经历的结果的差异时，编码UCP的基因是候选基因的优先级，并且可能导致β受益者的益处机制或对脂质代谢的不良反应。本文提出的研究代表了一项前瞻性药物遗传学研究，对糖尿病患者进行了广泛的表型，旨在洞悉我们先前与UCP多态性和不良β受体阻滞剂结果的机制和验证。在进行这项机械驱动的验证研究时，我们为将我们的发现转化为临床实践的框架。具体而言，该项目的目的是：1）使用UCP2-3基因型对β受体阻滞剂的治疗进行比较，以响应UCP2-3基因型，2）确定是否响应于β-基督治疗的糖尿病的人在UCP2-3 Genotypes和3 genotipers and beta-blocker治疗中是否响应于β-基督疗法的beta-blocker治疗，并评估32-3基因2）。这可能导致对CV药物的响应差异。这项研究具有重要的公共卫生影响，因为CVD是糖尿病死亡的主要原因。通过更好地理解为什么某些糖尿病患者对简历疗法的反应比其他患者更有利，我们可能能够更适当地治疗个别患者，从而改善结果。（抽象的结尾）