Role of inhibitory G protein signaling in regulating beta-cell function and survival in the type 1 diabetic state

项目摘要 国际糖尿病联合会估计，全球糖尿病负担已飙升至387 仅在美国，医疗费用就超过6120亿美元。糖尿病 对于这些个体，特别是I型糖尿病患者，管理是非常严格的， 提供有效的疾病维持手段。I型糖尿病患者的现行标准治疗 是用外源性胰岛素治疗，简单地说，这一措施可以让患者正常生活， 固有地解决与疾病相关的任何潜在病理。此外，很少有 I型糖尿病辅助治疗，其中没有一种已知可以改善β细胞健康和功能。我们 越来越多的证据表明，这种蛋白质，特别是α亚基（Gαz）， 在调节与I型糖尿病相关的多种β细胞病理的介导途径中发挥着显着作用。 因此，我们的长期目标是充分阐明Gαz在正常和非正常细胞中作用的信号传导机制。 和糖尿病β细胞，决定在糖尿病状态下功能失调的步骤， 为了预防和治疗的目的调节这些步骤。这项工作的总体目标是 追求我们目标的下一个合乎逻辑的步骤是描述β细胞Gαz在分子和细胞内的作用， 负责其对糖尿病病理生理学的影响的信号通路。我们的核心假设是， 活化的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 β细胞代偿的关键，最终导致β细胞功能障碍和β细胞质量损失， 糖尿病发病机制我们将检验我们的中心假设，从而实现本研究的目标。 应用，通过追求以下两个具体目标：（1）确定β细胞Gαz对β细胞的作用 （2）阐明β细胞Gαz对信号转导的影响 胰岛炎后介导β细胞存活的途径。随着这些目标的实现，我们预计 更全面地了解Gαz在健康和糖尿病β细胞中的作用。这样的结果 预计将在糖尿病领域取得重要的积极成果，因为Gαz是糖尿病领域的独特参与者。 整合的信号通路介导β细胞的功能和存活，为开发新的靶点。 用于预防和治疗I型糖尿病的治疗剂。

PROJECT SUMMARY The International Diabetes Federation estimates the global burden of diabetes to have skyrocketed to over 387 million people with healthcare costs reaching over $612 billion in the United States alone. Diabetes management for these individuals, particularly Type I Diabetic patients, is extremely rigorous and does not provide an efficient means of disease maintenance. Current standard of care for patients with Type I Diabetes is treatment with exogenous insulin, a measure, which simply put, allows patients to live normally, but does not inherently solve any of the underlying pathologies associated with the disease. Additionally, there are very few Type I Diabetes adjuvant therapeutics, none of which are known to improve β-cell health and function. We have a growing body of evidence that suggests that this protein, specifically the alpha subunit (Gαz) plays a notable role in mediating pathways regulating multiple β-cell pathologies associated with Type I Diabetes. Therefore, our long-term goal is to fully elucidate the signaling mechanism by which Gαz acts in both normal and diabetic β-cells, determining the steps that become dysfunctional in the diabetic state, and ultimately modulating these steps 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 role of β-cell Gαz on the molecular and cellular signaling pathways responsible for its impact on diabetes pathophysiology. Our central hypothesis is that activated β-cell Gαz negatively modulates specific intracellular and autocrine/paracrine signaling pathways critical for β-cell compensation, ultimately leading to β-cell dysfunction and loss of β-cell mass resulting in diabetes pathogenesis. We will test our central hypothesis and, thereby, accomplish the objective of this application, by pursuing the following two specific aims: (1) Determine the role of β-cell Gαz on β-cell function in the Type I Diabetic condition and (2) Elucidate the effect of β-cell Gαz on signaling pathways that mediate β-cell survival following insulitis. With the completion of these aims, we anticipate a much more complete understanding of the role of Gαz in both healthy and diabetic β-cells. Such results are anticipated to have an important positive outcome on the diabetes field, as Gαz is a unique player in the integrated signaling pathways that mediate β-cell function and survival, providing a new target for developing therapeutics for the prevention and treatment of Type I diabetes.