Pancreatic beta-cell CAMKII signaling under physiological and diabetic conditions

描述（由申请人提供）：胰腺β细胞胰岛素分泌是一种钙依赖性过程，在2型糖尿病进展期间受到干扰。钙/钙调蛋白依赖性激酶II（CaM激酶II）作为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也可以作为糖尿病进展期间发生的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鉴定CaM激酶II在生理和糖尿病条件下调节β-cII功能中的作用。该项目将利用一种新的转基因小鼠模型与四环素诱导的β细胞钙调蛋白激酶II抑制剂。用这种小鼠模型的初步研究已经确定，葡萄糖激活CaM激酶II增加β细胞钙进入和胰岛素分泌。基于这些初步的观察，我们假设CaM激酶II β细胞电活动和钙离子进入影响胰岛素分泌调节的葡萄糖依赖性。此外，我们提出，钙调素激酶II在2型糖尿病β细胞中起着相当大的调节作用，作为与糖尿病相关的钙，ROS和ER应激变化的信号转导介质。我们将这些假设与以下具体目标：1.确定在GSIS过程中，β细胞钙进入是如何被CaM激酶II调节的，以及这是如何影响葡萄糖稳态的。2.确定β-细胞CaM激酶II对2型糖尿病发病机制的影响。这些研究将是内源性β细胞CaM激酶II活性如何调节葡萄糖稳态的第一个测试。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。 公共卫生相关性：胰腺β细胞胰岛素分泌依赖于通过蛋白质（如CaM激酶II）的钙信号传导。揭示β-细胞CaM激酶II的功能将有助于深入了解钙依赖性胰岛素分泌的机制以及在糖尿病进展过程中这一机制如何变得有缺陷。该项目的结果将为治疗与2型糖尿病相关的bet-cell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.