Pancreatic beta-cell CAMKII signaling under physiological and diabetic conditions

描述(申请人提供)：胰岛β细胞胰岛素分泌是一个钙依赖的过程，在2型糖尿病的发展过程中变得不安。钙/钙调蛋白依赖性激酶II(CaM Kinase II)是葡萄糖诱导的钙内流和胰岛素分泌之间的信号中间体。在糖尿病的发展过程中，CaM激酶II也可能作为β细胞钙、活性氧(ROS)和内质网(ER)应激变化的信号通道。因此，这项建议的总体目标是确定在生理和糖尿病条件下CaM激酶II在调节β-CLL功能中的作用(S)。该项目将利用一种新的转基因小鼠模型，该模型带有四环素诱导的β细胞CaM激酶II抑制剂。对这一小鼠模型的初步研究已经确定，CaM激酶II的葡萄糖激活增加了β细胞钙进入和胰岛素分泌。在这些初步观察的基础上，我们假设CaM激酶IIβ细胞的电活动和钙内流影响胰岛素调节分泌的葡萄糖依赖。此外，我们认为，作为与糖尿病相关的钙、ROS和内质网应激变化的信号媒介，CaM激酶II在2型糖尿病的β细胞中起着相当大的调节作用。我们提出这些假设的具体目的如下：1.确定在GSIS过程中，CaM激酶II是如何调节β细胞钙离子进入的，以及这是如何影响血糖稳态的。2.测定β细胞钙调素激酶II在2型糖尿病发病机制中的作用(S)。这些研究将是关于内源性β细胞CaM激酶II活性如何调节葡萄糖稳态的第一次测试。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有重要的见解。这可能最终导致治疗2型糖尿病的新的治疗目标。 公共卫生相关性：胰腺β细胞胰岛素的分泌依赖于钙信号，通过蛋白质如CaM激酶II。揭示β细胞CaM激酶II的功能(S)将有助于深入了解依赖钙的胰岛素分泌的机制，以及在糖尿病进展过程中这种机制是如何变得缺陷的。该项目的结果将为治疗与2型糖尿病相关的下注细胞紊乱提供新的治疗策略的基础。

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. PUBLIC HEALTH RELEVANCE: Pancreatic beta-cell insulin secretion is dependent on calcium signaling through proteins such as such as CaM kinase II. Uncovering the function(s) of beta-cell CaM kinase II will lead to insights into the mechanisms involved in calcium dependent insulin secretion and how this becomes defective during the progression of diabetes. The results from this project will provide the basis of new therapeutic strategies for treating the bet-cell perturbations associated with type-2 diabetes.