Cyclin-Dependant Kinase 2 (CDK2) Function in Pancreatic Beta-Cells

描述（由申请人提供）：2型糖尿病涉及β细胞质量减少和胰岛素分泌受损，但质量和分泌之间的关系尚不清楚。细胞周期蛋白依赖性激酶（Cdks）调节细胞周期机制和β细胞增殖，并且可能是增加患者中β细胞质量的新药的可能靶点。然而，我们的新数据表明，在β细胞质量发生变化之前，中断Cdk 2信号传导会意外地破坏β细胞功能，这表明Cdk 2可能是β细胞增殖和分泌功能的整合剂。我们假设Cdk 2通过与离子通道、胰岛素受体信号通路和β细胞燃料代谢相互作用来影响β细胞功能。我们将利用β细胞中缺乏Cdk 2的小鼠模型，并使用新型代谢传感器结合膜片钳电生理学和胰岛素分泌测定来（1）确定Cdk 2在β细胞分泌途径中的靶点，（2）确定Cdk 2在控制β细胞生物能量学中的作用，以及（3）在人胰岛中建立Cdk 2途径并测试Cdk 2表达是否挽救糖尿病人胰岛中的β细胞功能。为了实现这些目标，我的导师Les Satin博士将为电生理学提供支持，我的共同导师Rane博士和合作者Bernal-Mizrachi博士将提供使用更先进的糖尿病模型的培训。在博姆糖尿病中心的协作环境将提供获得试剂和专业知识，将支持这项工作，并使其他小鼠模型的创建，以急性删除Cdk 2。我们提议的资源和培训将使我能够建立一条独立的研究路线，并将促进我的发展，生产力和独立性。此外，所获得的结果对于开发用于增加2型糖尿病患者的β细胞质量和分泌功能的新治疗方法将是重要的。

DESCRIPTION (provided by applicant):Type 2 diabetes involves reduced β-cell mass and impaired insulin secretion, but the relationship between mass and secretion is not well understood. Cyclin dependent kinases (Cdks) regulate cell cycle machinery and β-cell proliferation and could be possible targets for new drugs to increase β-cell mass in patients. Our new data, however, shows that interrupting Cdk2 signaling unexpectedly disrupts β-cell function long before changes in β-cell mass occur, suggesting Cdk2 might be an integrator of β-cell proliferation and secretory function. We hypothesize that Cdk2 affects β-cell function by interacting with ion channels, the insulin receptor signaling pathway, and β-cell fuel metabolism. We will take advantage of a mouse model lacking Cdk2 in its β-cells and use novel metabolic sensors combined with patch-clamp electrophysiology and insulin secretion assays to (1) determine the targets of Cdk2 in the β-cell secretory pathway, (2) determine the role of Cdk2 in controlling β-cell bioenergetics, and (3) establish the Cdk2 pathway in human islets and test whether Cdk2 expression rescues β-cell function in diabetic human islets. To accomplish these aims, my mentor, Dr. Les Satin, will provide support for the electrophysiology, and my co-mentor Dr. Rane and collaborator Dr. Bernal- Mizrachi will provide training in the use of more advanced diabetes models. The collaborative environment at the Brehm Diabetes Center will provide access to reagents and expertise that will support this work and enable the creation of other mouse models to acutely delete Cdk2. The access to resources and training we propose will allow me to establish an independent line of research and will promote my development, productivity, and independence. In addition, the results obtained will be important for the development of new treatments for increasing β-cell mass and secretory function in Type 2 diabetics.