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

抑制性 G 蛋白信号传导在调节 1 型糖尿病状态下 β 细胞功能和存活中的作用

• 批准号: 9261945
• 负责人: Rachel J Fenske
• 金额: $ 4.4万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261945
• 关键词: Address; Adjuvant; Apoptosis; B-Lymphocytes; Beta Cell; Biological; Blood; Blood Glucose; Cell Survival; Cell physiology; Cells; Chronic Disease; Complex; Coupled; Critical Pathways; Cyclic AMP; Data; Diabetes Mellitus; Diabetes prevention; Dinoprostone; Disease; Failure; Family; Financial compensation; Functional disorder; G-substrate; GTP-Binding Proteins; Goals; Health; Health Care Costs; Heterotrimeric GTP-Binding Proteins; Hormones; Hyperglycemia; Immune; In Vitro; Inbred NOD Mice; Individual; Infiltration; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; International; Intervention; Islets of Langerhans; Link; Longevity; Maintenance; Measures; Mediating; Molecular; Outcome; Pancreas; Paracrine Communication; Pathogenesis; Pathology; Pathway interactions; Patient Care; Patients; Pharmacologic Substance; Phenotype; Play; Prevention; Production; Prostaglandins; Proteins; Public Health; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Protein; Stream; Testing; Therapeutic; United States; Work; autocrine; base; cell type; cost; diabetes management; diabetes mellitus therapy; diabetic; diabetic patient; human disease; improved; improved outcome; in vivo; incretin hormone; insulin secretion; islet; mouse model; new therapeutic target; novel; novel strategies; receptor; response; standard of care; type I diabetic

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.

项目摘要 国际糖尿病联合会估计，糖尿病的全球烧伤已超过387 仅在美国，拥有医疗保健费用的百万人口就会达到6120亿美元。糖尿病 这些人的管理，尤其是I型糖尿病患者，非常严格，并且不会 提供有效的疾病维持手段。 I型糖尿病患者的当前护理标准 是用外源胰岛素治疗的，这是一种简单的措施，允许患者正常生活，但不能 固有地解决了与该疾病相关的任何基本病理。此外，很少 I型糖尿病可调疗法，尚无何种可以改善β细胞健康和功能。我们 有越来越多的证据表明该蛋白，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的显着作用。 因此，我们的长期目标是完全阐明GαZ在两种正常状态的信号传导机制 和糖尿病β细胞，确定在糖尿病状态下变得功能失调的步骤，最终 调节这些步骤以进行预防和治疗目的。这项工作的总体目标，即 追求我们目标的下一个逻辑步骤是表征β细胞GαZ在分子和细胞上的作用 信号通路负责其对糖尿病病理生理学的影响。我们的中心假设是 激活的β-cellGαZ负责调节特定的细胞内和自分泌/旁分泌信号通路 对于β细胞补偿至关重要，最终导致β细胞功能障碍和β细胞质量的损失，导致 糖尿病发病机理。我们将检验我们的中心假设，从而实现这一目标 通过追求以下两个特定目的，应用：（1）确定β细胞GαZ在β细胞上的作用 在I型糖尿病状态下的功能，（2）阐明了β细胞GαZ对信号的影响 胰岛炎后介导β细胞存活的途径。随着这些目标的完成，我们预计 对GαZ在健康和糖尿病β细胞中的作用更加完整地了解。这样的结果是 预计在糖尿病领域会有重要的积极结果，因为GαZ是独特的球员 介导β细胞功能和生存的集成信号通路，为发展提供了一个新的目标 预防和治疗I型糖尿病的治疗剂。