Pancreatic beta-cell CAMKII signaling under physiological and diabetic conditions

生理和糖尿病条件下的胰腺 β 细胞 CAMKII 信号传导

基本信息

批准号：
8479356
负责人：
David Aaron Jacobson
金额：
$ 7.53万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8479356
关键词：
Action Potentials Animal Model Animals Apoptosis Beta Cell Biological Assay Calcium Calcium Signaling Calmodulin Cell physiology Cells Cellular Stress Coupled Data Dependence Development Diabetes Mellitus Doxycycline Failure Fatty acid glycerol esters Functional disorder Glucose Glucose Intolerance Hyperglycemia Insulin Islets of Langerhans Lead Mediating Mediator of activation protein Mus Non-Insulin-Dependent Diabetes Mellitus Pancreas Pathogenesis Peptides Phosphotransferases Physiological Play Process Proteins Reactive Oxygen Species Regulation Role Ryanodine Receptor Calcium Release Channel Signal Pathway Signal Transduction Structure of beta Cell of islet Testing Tetracyclines Toxic effect Transgenic Animals Transgenic Mice base blood glucose regulation calmodulin-dependent protein kinase II diabetic endoplasmic reticulum stress feeding inhibitor/antagonist insight insulin secretion islet mouse model new therapeutic target novel novel therapeutics voltage

项目摘要

DESCRIPTION (provided by applicant): Pancreatic beta-cell insulin secretion is a calcium dependent process that becomes perturbed during the progression of type-2 diabetes. The calcium/calmodulin-dependent kinase II (CaM kinase II) serves as a signaling intermediate between glucose induced calcium entry and insulin secretion. CaM kinase II may also serve as a signaling conduit for the changes in beta-cell calcium, reactive oxygen species (ROS), and endoplasmic reticulum (ER) stress that occur during the progression of diabetes. Therefore, the overall objective of this proposal is to identify the role(s) of CaM kinase II in modulating beta-cll function under physiological and diabetic conditions. This project will utilize a novel transgenic mouse model with a tetracycline inducible beta-cell CaM kinase II inhibitor. Preliminary studies with this mouse model have determined that glucose activation of CaM kinase II increases beta-cell calcium entry and insulin secretion. Based upon these preliminary observations, we hypothesize that CaM kinase II beta-cell electrical activity and calcium entry influences the glucose dependence of insulin modulation of secretion. Furthermore, we propose that CaM kinase II plays a considerable regulatory role in the type-2 diabetic beta-cell as a signaling mediator for changes in calcium, ROS and ER-stress associated with diabetes. We will these hypotheses with the following specific aims: 1. Determine how beta-cell calcium entry is regulated by CaM kinase II during GSIS and how this influences glucose homeostasis. 2. Determine the influence(s) of beta-cell CaM kinase II on the pathogenesis of type-2 diabetes. These studies will be the first test of how endogenous beta-cell CaM kinase II activity modulates glucose homeostasis. Importantly, this project will make significant insights into mechanisms that modulate insulin secretion and beta-cell dysfunction during the progression of diabetes. This may ultimately lead to new therapeutic targets for treating type-2 diabetes.

描述（由申请人提供）：胰腺β细胞胰岛素分泌是一个钙依赖性过程，在2型糖尿病的进展过程中会受到干扰。钙/钙调蛋白依赖性激酶 II（CaM 激酶 II）充当葡萄糖诱导的钙进入和胰岛素分泌之间的信号传导中间体。 CaM 激酶 II 还可以作为糖尿病进展过程中发生的 β 细胞钙、活性氧 (ROS) 和内质网 (ER) 应激变化的信号传导管道。因此，本提案的总体目标是确定 CaM 激酶 II 在生理和糖尿病条件下调节 β-cll 功能中的作用。该项目将利用一种新型转基因小鼠模型，该模型具有四环素诱导型 β 细胞 CaM 激酶 II 抑制剂。对该小鼠模型的初步研究已确定，CaM 激酶 II 的葡萄糖激活会增加 β 细胞钙的进入和胰岛素的分泌。基于这些初步观察，我们假设 CaM 激酶 II β 细胞电活动和钙进入影响胰岛素分泌调节的葡萄糖依赖性。此外，我们认为 CaM 激酶 II 在 2 型糖尿病 β 细胞中发挥着相当大的调节作用，作为与糖尿病相关的钙、ROS 和 ER 应激变化的信号传导介质。我们将这些假设具有以下具体目标： 1. 确定 GSIS 期间 CaM 激酶 II 如何调节 β 细胞钙进入以及这如何影响葡萄糖稳态。 2. 确定 β 细胞 CaM 激酶 II 对 2 型糖尿病发病机制的影响。这些研究将首次测试内源性 β 细胞 CaM 激酶 II 活性如何调节葡萄糖稳态。重要的是，该项目将对糖尿病进展过程中调节胰岛素分泌和β细胞功能障碍的机制产生重要的见解。这可能最终导致治疗 2 型糖尿病的新治疗靶点。