G Protein Mediated Mechanisms of Beta Cell Death Dysfunction and Decompensation in Diabetes

糖尿病是一种代价高昂且复杂的慢性病，是一个严重的公共卫生问题。目前，流行率 退伍军人患糖尿病的风险约为25%，更多的退伍军人面临患糖尿病的风险 由于肥胖、衰老和不良的生活方式，以及接触到下列已知的糖尿病致化学物质 职责。未来几十年，患有糖尿病的退伍军人人数肯定会增加，因为 据估计，目前全世界患糖尿病的总风险接近50%。因此，开发新的 预防糖尿病以及识别和正确治疗糖尿病患者的方法是非常及时和 意义重大。根据定义，当β细胞分泌的胰岛素不足时，就会发生糖尿病。 胰腺适当地刺激身体细胞从血液中吸收葡萄糖，并切断更多葡萄糖的产生 葡萄糖。虽然它们有不同的病因，但1型(免疫介导的)和2型的病理生理学 (与肥胖相关的)糖尿病越来越多地与功能失调的细胞和分子信号联系在一起 作用于分泌胰岛素的β细胞的过程。一种分子是我们研究计划的基石， 称为Gαz，具有在影响β细胞功能的一个或多个信令过程中充当中枢的潜力， 复制、生长和/或生存。因此，针对这些功能失调的Gαz信号转导过程可能 潜在地有助于改善这两种类型糖尿病的功能性β细胞质量。我们的长期目标是充分 描述糖尿病状态下的G-α-z激活和信号通路在组织，组织，细胞， 和分子水平，指导我们为预防和治疗目的调节这一途径。 这项工作的总体目标，也是追求我们目标的下一个合乎逻辑的步骤，是描述 G-α-z信号对糖尿病影响的分子和细胞信号通路 病理生理学。我们的中心假设是激活的β-细胞Gαz负性调节特定的细胞内和 自分泌/旁分泌信号通路对β细胞补偿至关重要，最终导致β细胞死亡和 功能障碍，并加剧糖尿病的状况。我们将在多个临床前测试我们的中心假设 糖尿病模型，并由此通过追求以下步骤来实现本应用的目标 3个特异性目标：(1)确定EP3受体变异体/G-α-z偶联的不同效应 介导胰岛素胞吐的机制；(2)阐明cAMP- G-α-z对胰岛β细胞功能的独立调节；以及(3)阐明G-α-z信号对胰岛β细胞功能的影响 调节β细胞复制和存活的胰岛内通讯通路。随着工程的完成 在这些目标中，我们期待着对β细胞的作用及其信号有更全面的了解 糖尿病病理生理学中的分子。最终，分离Gαz对β细胞的影响并完全 研究其信号转导机制将有助于在β细胞中合理、特异地靶向该通路。 改善糖尿病β细胞功能障碍和功能性β细胞团丢失。

Diabetes is a costly and complex chronic illness and a serious public health problem. Currently, the prevalence of diabetes in the VA patient population is approximately 25%, with many more Veterans at risk for diabetes due to obesity, aging, and poor lifestyle, as well as exposure to known diabetogenic chemicals in the line of duty. The number of Veterans with diabetes is certain to increase over the next decades, as the children of today have an estimated overall lifetime risk of developing diabetes of nearly 50%. Therefore, developing new methods for preventing diabetes and identifying and properly treating diabetic patients is very timely and of great significance. By definition, diabetes occurs when insufficient insulin is produced from the β-cells of the pancreas to properly stimulate the body cells to take up glucose from the blood and shut off production of more glucose. While they have different etiologies, the pathophysiology of type 1 (immune-mediated) and type 2 (obesity-related) diabetes is increasingly being linked by dysfunctional cellular and molecular signaling processes that act in the insulin-secreting β-cells. One molecule that is a cornerstone of our research program, termed Gαz, has the potential to act as a hub in one or more signaling processes impacting on β-cell function, replication, growth and/or survival. Thus, targeting these dysfunctional Gαz signaling processes could potentially help to improve functional β-cell mass in both types of diabetes. Our long-term goal is to fully characterize the Gαz activation and signaling pathways in the diabetic state at the organismal, tissue, cellular, and molecular levels, guiding us in modulating this pathway for preventative and therapeutic purposes. The overall objective of this work, which is the next logical step in pursuit of our goal, is to characterize the molecular and cellular signaling pathways responsible for the impact of Gαz signaling on diabetes pathophysiology. Our central hypothesis is activated β-cell Gαz negatively modulates specific intracellular and autocrine/paracrine signaling pathways critical for β-cell compensation, ultimately leading to β-cell death and dysfunction and exacerbating the diabetic condition. We will test our central hypothesis in multiple pre-clinical models of diabetes and, thereby, accomplish the objective of this application, by pursuing the following three specific aims: (1) Determine the differential effects of EP3 receptor variant/Gαz coupling on mechansims mediating insulin exocytosis; (2) Elucidate the mechanisms underlying the cAMP- independent regulation of beta-cell function by Gαz; and (3) Elucidate the effect of Gαz signaling on intra-islet communication pathways that regulate beta-cell replication and survival. With the completion of these aims, we anticipate a much more complete understanding of the role of the β-cell and its signaling molecules in the pathophysiology of diabetes. Ultimately, isolating Gαz effects to the β-cell and fully characterizing its signaling mechanisms will aid in rationally and specifically targeting this pathway in the β-cell to improve diabetic β-cell dysfunction and loss of functional β-cell mass.