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：
8013710
负责人：
GEORGE G HOLZ
金额：
$ 7.94万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-04 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8013710
关键词：
Adenylate Cyclase Affinity Amides Anabolism Beta Cell Binding Biological Assay Blood Glucose Cell membrane Cell physiology Cells Complex 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 Tyrosine Kinase Proteins RALGDS gene Recruitment Activity Regulation Research Personnel Rodent Role Ryanodine Receptor Calcium Release Channel Ryanodine Receptors 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 insulin secretion interest islet kidney cell mimetics novel overexpression peptide analog phospholipase C epsilon programs receptor 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.

实验治疗学中的一个新兴主题涉及胰高血糖素样肽-1-(7-36)-的使用酰胺 (GLP-1) 及其合成肽类似物（“肠促胰岛素模拟物”）可降低血糖水平 2 型糖尿病受试者。 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。鉴于既定的 GLP-1 对于治疗糖尿病的重要性，我们的实验室有兴趣定义该信号 β 细胞 GLP-1 受体 (GLP-1-R) 的转导特性。为此，我们重点关注了新发现的信号传导机制，使用第二信使 cAMP 来激活 cAMP- 受调节的鸟嘌呤核苷酸交换因子指定为 Epad 和 Epac2（交换蛋白直接由环 AMP 激活）。我们的研究使我们假设 GLP-1，一种 cAMP 升高蛋白激素，刺激 Ca2+ 依赖性胰岛素分泌，并且这种促胰岛素作用不是介导的简单地通过蛋白激酶A (PKA)，也可以通过Epac。检验我们关于假定角色的假设 Epac 在 GLP-1-R 介导的信号转导中的作用，该项目的具体目标是： 1) 确定是否 GLP-1 使用 Epad 和/或 Epac2 通过 Ca2+ 诱导 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 受体或兰尼碱受体，2) 评估 Rap 家族 GTPases 在 ER Ca2"1" 过程中发挥的作用动员，特别强调 Rap1 作为中介连接激活的潜在作用 Epac 刺激磷脂酶 C-ε，并且 3) 确定新信号传导的性质 β 细胞生长因子和受体酪氨酸激酶利用 Ras GTPases 的机制将 Epac2 招募到质膜，Epac2 与其假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。我们希望为新型血液的“抗糖尿病”特性建立分子基础激活 GLP-1-R 并刺激胰腺胰岛素分泌的降糖药。