Molecular Basis of Antidiabetogenic Hormone Action

抗糖尿病激素作用的分子基础

基本信息

批准号：
7340179
负责人：
GEORGE G HOLZ
金额：
$ 1.62万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-15 至 2008-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7340179
关键词：
Adenylate Cyclase Affinity Amides Anabolism Beta Cell Binding Biological Assay Blood Glucose Cell membrane Cell physiology Cells Class Complex Condition Couples Cyclic AMP Cyclic AMP-Dependent Protein Kinases Diabetes Mellitus Dominant-Negative Mutation EGF gene Electric Capacitance Endoplasmic Reticulum Epitopes Exocytosis Family Funding GLP-I receptor Generations Goals Growth Factor Growth Factor Receptors Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Hormones Human In Vitro Insulin Insulin-Like Growth Factor I Investigation Islets of Langerhans Knockout Mice Laboratories Lead Link Measurement Measures Mediating Membrane Molecular Nature Pancreas Patch-Clamp Techniques Play Process Production Property Protein Isoforms Protein Overexpression Protein Tyrosine Kinase Proteins RALGDS gene Recruitment Activity Regulation Research Personnel Rodent Role Ryanodine Receptor Calcium Release Channel Second Messenger Systems Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Source Stimulus Structure of beta Cell of islet Testing Therapeutic Transfection adenosine cyclic-3&apos ,5&apos -monophosphate binding proteins analog base cell growth diabetic glucagon-like peptide 1 inositol-1,4,5-triphosphate receptor insulin secretion interest islet kidney cell mimetics novel peptide analog phospholipase C epsilon programs ral Guanine Nucleotide Exchange Factor second messenger sensor sulfonylurea receptor synthetic peptide voltage

项目摘要

An emerging theme in experimental therapeutics concerns the use of glucagon-like peptide-1-(7-36)- amide (GLP-1) and its synthetic peptide analogs (the "incretin mimetics") to lower levels of blood glucose in Type 2 diabetic subjects. This action of GLP-1 results, at least in part, from its ability to stimulate the secretion of insulin from pancreatic beta cells located in the islets of Langerhans. Given the established importance of GLP-1 for the treatment of diabetes, our laboratory is interested in defining the signal transduction properties of the beta cell GLP-1 receptor (GLP-1-R). To this end, we have focused on a newly-discovered signaling mechanism that uses the second messenger cAMP to activate cAMP- regulated guanine nucleotide exchange factors designated as Epad and Epac2 (the Exchange Proteins directly Activated by Cyclic AMP). Our studies lead us to Hypothesize that GLP-1, a cAMP-elevating hormone, stimulates Ca2+-dependent insulin secretion, and that this insulinotropic action is mediated not simply by protein kinase A (PKA), but also by Epac. To test our Hypothesis concerning the putative role of Epac in GLP-1-R-mediated signal transduction, the Specific Aims of this project are to: 1) determine if GLP-1 uses Epad and/or Epac2 to mobilize intracellular Ca2+ via a process of Ca2+-induced Ca2+ release (CICR) that originates at the endoplasmic reticulum (ER) and which may involve IP3 receptors or ryanodine receptors, 2) assess what role Rap family GTPases play in the process of ER Ca2"1" mobilization, with special emphasis on the potential role of Rap1 as an intermediary linking activation of Epac to the stimulation of phospholipase C-epsilon, and 3) determine the nature of a novel signaling mechanism by which beta cell growth factors and receptor tyrosine kinases utilize the Ras GTPases to recruit Epac2 to the plasma membrane where an interaction of Epac2 with its putative effector molecule the sulfonylurea receptor-1 (SUR1) occurs. The Relevance of this line of investigation is fully apparent. We wish to establish the molecular basis for "antidiabetogenic" properties of a new class of blood glucose-lowering agents that activate the GLP-1-R and which stimulate pancreatic insulin secretion.

实验疗法的一个新兴主题涉及使用胰高血糖素样肽1-（7-36） - 酰胺（GLP-1）及其合成肽类似物（“降直型蛋白模拟物”）至较低的血糖水平在2型糖尿病患者中。 GLP-1的这种作用至少部分是由于其刺激的能力来自位于Langerhans胰岛中胰腺β细胞的胰岛素的分泌。鉴于已建立 GLP-1对于治疗糖尿病的重要性，我们的实验室有兴趣定义信号 β细胞GLP-1受体（GLP-1-R）的转导特性。为此，我们专注于新发现的信号传导机制，该机制利用第二信使训练营激活营地 - 指定为EPAD和EPAC2的调节鸟嘌呤核苷酸交换因子（交换蛋白直接被循环AMP激活）。我们的研究导致我们假设GLP-1是一个训练营激素，刺激Ca2+依赖性胰岛素分泌，并且这种胰岛素作用不是介导的仅通过蛋白激酶A（PKA），也可以通过EPAC。测试我们关于假定角色的假设 GLP-1-R介导的信号转导中EPAC的特定目的是：1）确定是否确定 GLP-1使用EPAD和/或EPAC2通过Ca2+诱导的Ca2+的过程动员细胞内Ca2+ 起源于内质网（ER）的释放（CICR），可能涉及IP3受体或 ryanodine受体，2）评估RAP家族GTPases在ER Ca2“ 1”过程中的作用动员，特别强调了Rap1作为中介的潜在作用 EPAC刺激磷脂酶C-Epsilon，3）确定新型信号的性质 β细胞生长因子和受体酪氨酸激酶利用RAS GTPases的机制招募EPAC2到质膜，其中EPAC2与推定的效应分子的相互作用磺酰脲受体1（SUR1）发生。这种调查的相关性是完全明显的。我们希望建立新血液的“抗糖尿病生成”特性的分子基础降糖剂激活GLP-1-R并刺激胰腺胰岛素分泌。