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：
7194712
负责人：
GEORGE G HOLZ
金额：
$ 29.58万
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 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7194712
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

DESCRIPTION (provided by applicant): 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 Epac1 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 Epac1 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+ 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.

描述（由申请人提供）：实验治疗中的一个新兴主题涉及使用胰糖明样肽-1-（7-36）-Amide（GLP-1）及其合成肽类似物（“肠脉蛋白模拟物”）在2型2型糖尿病患者中较低的血糖水平。 GLP-1的这种作用至少部分是由于它刺激位于Langerhans胰岛中胰腺β细胞的胰岛素分泌的能力。鉴于GLP-1在治疗糖尿病方面具有确定的重要性，我们的实验室有兴趣确定β细胞GLP-1受体（GLP-1-R）的信号转导特性。为此，我们专注于一种新发现的信号传导机制，该机制使用第二信使训练营激活了指定为EPAC1和EPAC2的cAMP调节的鸟嘌呤核苷酸交换因子（由环状AMP直接激活的交换蛋白）。我们的研究使我们假设GLP-1是一种cAMP升高的激素，刺激了Ca2+依赖性胰岛素的分泌，并且这种胰岛素性作用不仅是由蛋白激酶A（PKA）介导的，而且还由EPAC介导。 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 Epac1 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受体，2）评估RAP家族GTPases在ER CA2+动员过程中的作用，特别强调RAP1作为将EPAC激活与磷脂酶C-Epsilon刺激的中介作用的潜在作用，以及3）确定β细胞生长因子和受体企业酶的新型信号机制的性质2）膜中EPAC2与推定的效应分子的相互作用发生磺酰脲受体1（SUR1）。这种调查的相关性是完全明显的。我们希望建立一种新的降血葡萄糖剂的“抗糖尿病生成”特性的分子基础，该特性激活GLP-1-R并刺激胰腺胰岛素分泌。