Pharmacogenomics of Thiazolidinedione Response

噻唑烷二酮反应的药物基因组学

• 批准号: 7486311
• 负责人: Soren Snitker
• 金额: $ 57.39万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486311
• 关键词: 2,4-thiazolidinedione; Abdomen; Adipocytes; Adult; Affect; African American; Aftercare; Age; Agonist; American; Arts; Body fat; Body mass index; Candidate Disease Gene; Caucasians; Caucasoid Race; Class; Clinical; Computer Simulation; DNA; Data; Development; Diabetes Mellitus; Drug usage; Dual-Energy X-Ray Absorptiometry; Elements; Exhibits; Fatty acid glycerol esters; Gender; Gene Expression; Gene Frequency; Genes; Genetic; Genotype; Glycosylated hemoglobin A; Haplotypes; Health; High Density Lipoproteins; IL6 gene; Individual; Inflammatory; Insulin Resistance; Intervention; Leptin; Ligands; Lipids; Lipolysis; Measures; Metabolic syndrome; Metabolism; Mexican Americans; Microarray Analysis; Molecular; Molecular Genetics; Molecular Profiling; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Nucleic Acid Regulatory Sequences; PPAR gamma; Particle Size; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Physiological; Pioglitazone; Plasminogen Activator Inhibitor 1; Polymerase Chain Reaction; Population; Prevention; Purpose; Recruitment Activity; Regulation; Research; Research Personnel; Sampling; Serum; Structure; Testing; Thiazolidinediones; Time; Tissue Sample; Tissues; Variant; Woman; adipokines; adiponectin; base; cDNA Arrays; diabetes prevention program; diabetic; functional genomics; glucose uptake; impaired glucose tolerance; innovation; insight; insulin sensitivity; insulin sensitizing drugs; insulin signaling; interest; intravenous glucose tolerance test; lipid biosynthesis; low density lipoprotein triglyceride; prescription document; prescription procedure; programs; receptor; response; rosiglitazone; trait; troglitazone

DESCRIPTION (provided by applicant): Thiazolidinediones (TZDs) are a group of insulin-sensitizing drugs useful in the treatment and possibly in the prevention of type 2 diabetes mellitus. However, approximately 1/3 of individuals treated with TZDs show little or no clinical response. Responsiveness cannot be predicted from simple clinical parameters. Therefore, insight into the genetic mechanisms governing responsiveness will further rational prescription practices and may inform the development of new drugs. The purpose of the proposed research is to uncover predictors of response by administering a TZD to pre-diabetic individuals, defining the pathways governing clinical response, and locating crucial variants in the implicated genes. As an extension of our ongoing Pharmacogenomics of PPAR-gamma project, the Specific Aims of the proposed research are threefold. (1) First, we will characterize extensively the response of 75 individuals to 3 months of treatment with the TZD rosiglitazone. This characterization, which will be performed identically before and after treatment, focuses on insulin sensitivity, mechanistic precursors of clinical response observed in fat and muscle tissue samples, and gene expression profiles from these tissues obtained by microarray analysis. (2) Once we have identified the pathways whose regulation is correlated with TZD response, we will define sequence variation and haplotype structure of 100 candidate genes in these pathways. (3) Lastly, we will determine which sequence variants influence TZD response through association analysis of SNPs/haplotypes in our population and other populations treated with a TZD (Diabetes Prevention Program and TRIPOD/PI POD). The proposed studies will provide important insights into the mechanisms of action and determinants of responsiveness to a widely prescribed diabetes medication, as well as into insulin resistance in general. Insulin resistance is a central element of the metabolic syndrome, a constellation of adverse health factors that affects one in five adult Americans.

描述（由申请人提供）： 噻唑烷二酮类（TZD）是一组可用于治疗并可能预防 2 型糖尿病的胰岛素增敏药物。然而，大约 1/3 接受 TZD 治疗的个体表现出很少或没有临床反应。无法从简单的临床参数预测反应性。因此，深入了解控制反应性的遗传机制将进一步促进合理的处方实践，并可能为新药的开发提供信息。拟议研究的目的是通过对糖尿病前期个体施用 TZD、定义控制临床反应的途径以及定位相关基因中的关键变异来揭示反应的预测因子。作为我们正在进行的 PPAR-gamma 药物基因组学项目的延伸，拟议研究的具体目标有三个。 (1) 首先，我们将广泛描述 75 名个体对 TZD 罗格列酮治疗 3 个月的反应。该表征将在治疗前后进行相同的操作，重点关注胰岛素敏感性、在脂肪和肌肉组织样本中观察到的临床反应的机制前兆，以及通过微阵列分析获得的这些组织的基因表达谱。 (2)一旦我们确定了与TZD反应相关的调控途径，我们将定义这些途径中100个候选基因的序列变异和单倍型结构。 (3) 最后，我们将通过对我们人群和接受 TZD（糖尿病预防计划和 TRIPOD/PI POD）治疗的其他人群中的 SNP/单倍型进行关联分析，确定哪些序列变异影响 TZD 反应。拟议的研究将为广泛使用的糖尿病药物的作用机制和反应性决定因素以及一般胰岛素抵抗提供重要见解。胰岛素抵抗是代谢综合征的核心要素，代谢综合征是影响五分之一的美国成年人的一系列不利健康因素。