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）：实验治疗学中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（“肠促胰岛素模拟物”）来降低2 型糖尿病受试者的血糖水平。 GLP-1 的这种作用至少部分是由于其刺激位于朗格汉斯岛的胰腺 β 细胞分泌胰岛素的能力。鉴于 GLP-1 对于治疗糖尿病的重要性已被证实，我们的实验室有兴趣定义 β 细胞 GLP-1 受体 (GLP-1-R) 的信号转导特性。为此，我们重点研究了一种新发现的信号传导机制，该机制使用第二信使 cAMP 来激活 cAMP 调节的鸟嘌呤核苷酸交换因子，称为 Epac1 和 Epac2（环 AMP 直接激活的交换蛋白）。我们的研究使我们假设 GLP-1（一种 cAMP 升高激素）可刺激 Ca2+ 依赖性胰岛素分泌，并且这种促胰岛素作用不仅由蛋白激酶 A (PKA) 介导，还由 Epac 介导。为了检验我们关于 Epac 在 GLP-1-R 介导的信号转导中的假定作用的假设，该项目的具体目标是：1) 确定 GLP-1 是否使用 Epac1 和/或 Epac2 通过一个过程动员细胞内 Ca2+ Ca2+ 诱导的 Ca2+ 释放 (CICR) 起源于内质网 (ER)，可能涉及 IP3 受体或兰尼丁受体， 2) 评估 Rap 家族 GTPases 在 ER Ca2+ 动员过程中发挥的作用，特别强调 Rap1 作为连接 Epac 激活与磷脂酶 C-ε 刺激的中介的潜在作用，以及 3) 确定β 细胞生长因子和受体酪氨酸激酶利用 Ras GTPases 将 Epac2 募集到质膜上的新型信号传导机制，其中 Epac2 与其推定的效应分子相互作用磺酰脲受体 1 (SUR1) 发生。这一调查路线的相关性是完全显而易见的。我们希望为一类新型降血糖药物的“抗糖尿病”特性建立分子基础，该降血糖药物可激活 GLP-1-R 并刺激胰腺胰岛素分泌。