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Proteomics Reagents in Diabetes & Metabolism

糖尿病中的蛋白质组学试剂

基本信息

批准号：
6623466
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
项目类别：
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

项目摘要

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）：糖尿病是一种主要的健康问题，美国和发展中国家的威胁。试点与可行性研究了天然蛋白质合成的应用糖尿病的研究。我们预计，拟议的研究将促进糖尿病相关基因产物的结构分析，用于蛋白质组学的新型试剂。两年的支持旨在证明这种方法的承诺。目标1集中在胰岛素信号通路线虫C.优雅的这条通路部分控制着衰老和寿命，通过对道尔州的监管。梭线虫基因组包含34个假定的胰岛素样基因和人胰岛素的单一直向同源物受体（命名为DAF-2）。因为胰岛素样序列高度不同于哺乳动物胰岛素，其分类是有争议的。我们建议（a）合成代表性C。线虫多肽，（B）测定它们的结构，和（c）表征它们的生化功能（结合到和调节DAF-2酪氨酸激酶受体）。胰岛素信号 C.秀丽线虫有机会将强大的遗传联合收割机，生物化学和结构工具在一个易于处理的模式生物。目标2重点一种新发现的哺乳动物激素，由脂肪细胞分泌，多肽阻断胰岛素作用，因此与临床联系有关人类肥胖和II型糖尿病之间的联系。我们建议（a）合成二苯甲酰胺，（B）确定其结构，（c）表征结构-功能关系，和（d）创建新的用于克隆推定的IgG 4受体的试剂。拟议的研究有翻译潜力作为新的人类疗法的基础。总的来说，利用天然生物技术快速大规模合成富含半胱氨酸的新基因产物肽连接有望加快结构和功能分析，糖尿病相关的调节途径。拟议的试点研究将剖析衰老和老化遗传模型中的胰岛素信号通路（目的1）以及人类代谢稳态和胰岛素抵抗的新机制肥胖