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

G蛋白介导的糖尿病β细胞死亡功能障碍和失代偿机制

• 批准号: 10265403
• 负责人: Michelle E Kimple
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265403
• 关键词: Aging; Alpha Cell; B-Cell Activation; Beta Cell; Blood Circulation; Blood Glucose; C-terminal; Caring; Cell Death; Cell membrane; Cell physiology; Cells; Chemicals; Child; Chronic Disease; Communication; Complex; Coupled; Coupling; Critical Pathways; Cyclic AMP; Data; Diabetes Mellitus; Diabetes prevention; Dinoprostone; Etiology; Exocytosis; Exposure to; Failure; Financial compensation; Fluorescence Resonance Energy Transfer; Functional disorder; GLP-I receptor; GTP-Binding Protein alpha Subunits; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; General Population; Glucose; Goals; Growth; Health; Hormones; Human; Hyperglycemia; Image; Immune; Individual; Insulin; Islet Cell; Knockout Mice; Label; Laboratories; Life Style; Link; Longevity; Mediating; Membrane; Methods; Microscopy; Molecular; Mus; Obesity; Pancreas; Paracrine Communication; Pathway interactions; Pharmaceutical Preparations; Pre-Clinical Model; Prediabetes syndrome; Prevalence; Prevention therapy; Process; Production; Proteins; Public Health; RNA Splicing; Regulation; Research; Residual state; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Structure of beta Cell of islet; Sulfonylurea Compounds; Tail; Testing; Therapeutic; Time; Tissues; Variant; Veterans; Work; autocrine; base; cell type; cellular targeting; cost; diabetes risk; diabetic; diabetic patient; diabetogenic; experimental study; functional loss; glucagon-like peptide 1; improved; innovation; islet; lifetime risk; military veteran; mimetics; mouse model; novel; overexpression; paracrine; patch clamp; patient population; preservation; prevent; programs; receptor; recruit; therapeutic target

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.

糖尿病是一种昂贵且复杂的慢性病，​​也是一个严重的公共卫生问题。目前，患病率 VA患者人群中的糖尿病大约为25％，还有更多的退伍军人处于糖尿病的风险 由于肥胖，衰老和生活方式差，以及暴露于已知的糖尿病性化学物质中 责任。随着未来几十年，糖尿病的退伍军人人数肯定会增加 如今，估计有糖尿病近50％的总体终生风险。因此，开发新的 预防糖尿病和识别和适当治疗糖尿病患者的方法非常及时， 重要的意义。根据定义，当胰岛素从β细胞产生不足时，会发生糖尿病 胰腺适当刺激身体细胞以从血液中吸收葡萄糖并关闭更多的产生 葡萄糖。尽管它们具有不同的病因，但1型（免疫介导）和2型的病理生理学 （与肥胖相关的）糖尿病越来越多地通过功能失调的细胞和分子信号连接 作用于分泌胰岛素的β细胞的过程。一个分子是我们研究计划的基石， 称为GαZ，有可能在一个或多个影响β细胞功能的信号传导过程中充当集线器， 复制，生长和/或生存。这是针对这些功能障碍的GαZ信号传导过程的 有助于改善两种糖尿病的功能性β细胞质量。我们的长期目标是完全 表征在有机体，组织，细胞， 和分子水平，指导我们调节该途径以进行预防和治疗目的。 这项工作的总体目标，这是追求我们目标的下一个逻辑步骤，是表征 负责GαZ信号对糖尿病的影响的分子和细胞信号传导途径 病理生理学。我们的中心假设被激活了β-cellGαZ，对特定的细胞内和 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状况。我们将在多个临床前测试我们的中心假设 糖尿病的模型，从而通过追求以下内容来实现本应用的目标 三个特定目的：（1）确定EP3受体变体/GαZ耦合对 介导胰岛素胞吐作用的机制； （2）阐明营地的基础机制 GαZ对Beta细胞功能的独立调节； （3）阐明GαZ信号对 调节β细胞复制和生存的伊斯兰内通信途径。完成 在这些目标中，我们预计对β细胞的作用及其信号的作用有更完整的了解 糖尿病病理生理学中的分子。最终，将GαZ效应分离为β细胞和完全 表征其信号传导机制将有助于合理地，专门针对β细胞中的这一途径 改善糖尿病β细胞功能障碍和功能性β细胞质量的丧失。