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Coordinated regulation of signaling events for insulin biosynthesis and secretion

胰岛素生物合成和分泌信号事件的协调调节

基本信息

批准号：
8207258
负责人：
Gen-Sheng Feng
金额：
$ 32.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8207258
关键词：
Address Alleles Anabolism Automobile Driving Beta Cell Binding Cell Differentiation process Cell Line Cell Proliferation Cell physiology Cells Complement Data Development Diabetes Mellitus Enzymes Epidermal Growth Factor Etiology Event Failure Functional disorder Gene Targeting Genes Glucose Goals Growth Growth Factor Growth Factor Receptors Hormones In Vitro Indium Insulin Insulin Receptor Insulin Signaling Pathway Islet Cell Knock-out Knowledge Lead Mediating Metabolic Diseases Molecular Mus Mutant Strains Mice Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Pancreas Pathogenesis Pathway interactions Physiological Production Protein Tyrosine Phosphatase Proteins Regulation Role Scheme Science Signal Pathway Signal Transduction Small Interfering RNA System Techniques Testing Text Tissues Work base blood glucose regulation cell type cytokine design impaired glucose tolerance in vivo insulin secretion insulin signaling insulinoma mature animal mouse model novel precursor cell research study response

项目摘要

Summary: The goal of this project is to decipher molecular signaling mechanisms for control of insulin biosynthesis and secretion, and the immediate focus is on dissecting the function of Shp2 tyrosine phosphatase in orchestrating signaling cascades in ¿ cells. Although pancreatic ¿ cell failure is a critical component in all forms of diabetes, the molecular basis underlying ¿ cell dysfunction is poorly understood. This is mainly because that little is known for the cytoplasmic components mediating glucose and insulin signals in ¿-cells. Shp2 is a cytoplasmic tyrosine phosphatase with two SH2 domains that is implicated in regulation and coordination of signaling pathways. In particular, Shp2 has been shown to promote insulin-stimulated Erk activation in vitro, although the physiological significance of Shp2 function in insulin signaling is unclear. In recent studies, we have successfully created a conditional Shp2 knockout allele, Shp2flox, in mice, which allows us to investigate specific Shp2 functions in a specific cell type or tissue in vivo. We have generated mutant mice with Shp2 deleted in mature ¿-cells or in Pdx1+ pancreatic precursor cells, and will characterize these novel mouse models to test the working hypothesis that Shp2 acts to coordinate and control the strength of several signaling pathways in orchestrating insulin biosynthesis and secretion in ¿-cells. In complement with the gene targeting approach in vivo, we will also use siRNA- mediated gene knockdown technique to decipher the molecular signaling mechanisms in ¿ cells. Our specific aims are: 1) to determine the physiological role of Shp2 in ¿-cell function and glucose homeostasis; 2) to dissect the molecular mechanism for Shp2 action in ¿-cells; and 3) to investigate the Shp2 function in pancreatic development and ¿-cell regeneration. Successful completion of the proposed experiments will fill in a gap in our knowledge for coordinated regulation of cytoplasmic signaling events in ¿-cells, and may even lead to a new paradigm on regulation of ¿-cell functions in glucose homeostasis and also in pathogenesis of type 2 diabetes.

简介: