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.

糖尿病是一种昂贵而复杂的慢性疾病，也是一个严重的公共卫生问题。目前， VA患者人群中糖尿病的比例约为25%，更多的退伍军人有糖尿病的风险 由于肥胖、衰老和不良的生活方式，以及暴露于已知的致糖尿病化学物质， 的义务.糖尿病退伍军人的数量在未来几十年肯定会增加，因为他们的孩子 据估计，今天的人一生中患糖尿病的风险接近50%。因此，开发新的 预防糖尿病和识别并适当治疗糖尿病患者的方法是非常及时的， 意义重大。根据定义，糖尿病发生时，β细胞产生的胰岛素不足， 胰腺适当地刺激身体细胞从血液中摄取葡萄糖，并停止产生更多的葡萄糖。 葡萄糖虽然它们有不同的病因，但1型（免疫介导）和2型（免疫介导）的病理生理学 （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 在胰岛素分泌β细胞中起作用的过程。一种分子是我们研究计划的基石， 称为Gαz，有可能在影响β细胞功能的一个或多个信号传导过程中充当枢纽， 复制、生长和/或存活。因此，针对这些功能失调的Gαz信号传导过程， 可能有助于改善两种类型糖尿病的功能性β细胞群。我们的长期目标是， 在生物体、组织、细胞， 和分子水平，指导我们调节这一途径，以达到预防和治疗的目的。 这项工作的总体目标，这是追求我们目标的下一个合乎逻辑的步骤，是描述 负责Gαz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细胞外信号， 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， 功能障碍和加重糖尿病病情。我们将在多个临床前研究中检验我们的中心假设。 糖尿病模型，从而实现本申请的目的， 三个具体目标：（1）确定EP 3受体变体/Gαz偶联对 （2）阐明cAMP-β-葡萄糖调节胰岛素分泌的机制。 Gαz对β细胞功能的独立调节;（3）阐明Gαz信号转导对β细胞功能的影响。 调节β细胞复制和存活的胰岛内通讯途径。完成后 在这些目标中，我们期望对β细胞的作用及其信号传导有更全面的了解 糖尿病的病理生理学分子。最终，将Gαz效应分离到β细胞， 表征其信号传导机制将有助于合理和特异性地靶向β细胞中的该途径。 以改善糖尿病β细胞功能障碍和功能性β细胞团的损失。