Proteomics Reagents in Diabetes & Metabolism

糖尿病中的蛋白质组学试剂

• 批准号: 6466030
• 负责人: MICHAEL Aaron WEISS
• 金额: $ 15.3万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6466030
• 关键词: Caenorhabditis elegans; X ray crystallography; adipocytes; biological signal transduction; genome; hormone regulation /control mechanism; insulin; insulin receptor; insulin sensitivity /resistance; insulinlike factor; microarray technology; noninsulin dependent diabetes mellitus; nuclear magnetic resonance spectroscopy; obesity; peptide hormone metabolism; protein biosynthesis; protein structure function; proteomics; receptor binding; selenomethionine

DESCRIPTION (Provided by applicant): Diabetes mellitus poses a major health threat in the United States and developing world. This Pilot & Feasibility proposal investigates the application of total protein synthesis by native ligation to diabetes research. We anticipate that the proposed studies will facilitate structural analysis of diabetes-related gene products and provide novel reagents for proteomics. Two years of support are sought to demonstrate the promise of this approach. Aim 1 focusses on the insulin signaling pathway in the nematode C. elegans. This pathway controls aging and life span, in part through regulation of the dauer state. The C. elegans genome contains 34 putative insulin-like genes and a single orthologue of the human insulin receptor (designated daf-2). Because the insulin-like sequences are highly divergent from mammalian insulins, their classification is controversial. We propose to (a) synthesize representative C. elegans polypeptides, (b) determine their structures, and (c) characterize their biochemical function (binding to and regulation of the daf-2 tyrosine kinase receptor). The insulin signaling pathway in C. elegans promises an opportunity to combine powerful genetic, biochemical, and structural tools in a tractable model organism. Aim 2 focuses on a newly described mammalian hormone, resistin. Secreted by adipocytes, this polypeptide blocks insulin action and thus is implicated in the clinical link between human obesity and Type II diabetes mellitus. We propose to (a) synthesize resistin, (b) determine its structure, (c) characterize structure-function relationships by scanning mutagenesis, and (d) create novel reagents for cloning the putative resistin receptor. The proposed studies have translational potential as a basis for new human therapeutics. In summary, rapid and large-scale synthesis of novel cysteine-rich gene products by native peptide ligation promises to expedite structural and functional analysis of diabetes-related regulatory pathways. The proposed pilot studies will dissect an insulin signaling pathway in a genetic model of senescence and aging (Aim 1) and a novel mechanism of metabolic homeostasis and insulin resistance in human obesity.

描述（由申请人提供）：糖尿病是主要的健康问题