Ion channel regulation of pancreatic islet cell function

离子通道对胰岛细胞功能的调节

• 批准号: 10249948
• 负责人: Rajan Sah
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249948
• 关键词: Adipose tissue; Aging; Anions; Attention; B Cell Proliferation; B-Lymphocytes; Beta Cell; Biology; C-terminal; Cadaver; Cell membrane; Cell physiology; Cellular biology; Chlorides; Closure by clamp; Complex; Coupling; Cryoelectron Microscopy; Data; Diabetes Mellitus; Diabetes prevention; Disease; Equilibrium; Exhibits; FRAP1 gene; Failure; Glucose; Glucose Intolerance; Health; Heart Diseases; Human; Hyperglycemia; Immunoprecipitation; Impairment; In Vitro; Insulin; Ion Channel; Islets of Langerhans; Kidney Diseases; Knowledge; Label; Leucine-Rich Repeat; Long-Term Effects; Mass Spectrum Analysis; Measures; Mediating; Membrane Potentials; Microscopy; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Phase; Population; Protein Family; Proto-Oncogene Proteins c-akt; Reagent; Regulation; Reporting; Research; Retinal Diseases; Signal Pathway; Signal Transduction; Societies; Stroke; Structure of beta Cell of islet; Swelling; Testing; Therapeutic; Time; Vesicle; Veterans; cell growth; experimental study; gain of function; in vivo; innovation; insight; insulin secretion; insulin sensitivity; islet; knowledge base; member; military veteran; mortality; mutant; novel; novel therapeutic intervention; patch clamp; preservation; therapeutic target; trafficking; voltage; voltage clamp

Project Summary/Abstract It is estimated that 1 in 4 Veterans suffer from diabetes, and, in the Veteran population, this is largely Type 2 diabetes. This condition drives heart disease, stroke, retinopathy, nephropathy and neuropathy, all of which are a cause of significant morbidity and mortality among our Veterans. As such, understanding the biology of diabetes, discovering novel molecules that regulate b-cell function and developing innovative therapeutic approaches will have a significant impact on the health of our aging veteran population. Type 2 diabetes is characterized by both a loss of insulin sensitivity and, ultimately, a relative loss of insulin-secretion from the pancreatic b-cell. Insulin secretion from the pancreatic b-cell is triggered by Ca2+ influx through voltage-gated Ca2+ channels (VGCC) to trigger insulin vesicle fusion with the b-cell plasma membrane. We recently reported that SWELL1 (LRRC8a), a member of the Leucine Rich Repeat Containing protein family, is required for ICl,SWELL in β-cells. SWELL1-mediated ICl,SWELL activates upon b-cell swelling induced by glucose import, and this generates a depolarizing current contributing to VGCC activation, thereby regulating insulin secretion and systemic glycemia. Indeed, mice with SWELL1-deficient β-cells exhibit impaired glucose- stimulated insulin secretion and glucose intolerance. Moreover, we find that ICl,SWELL is reduced in both mouse and humans in the context of Type 2 diabetes (T2D) indicating that reduced SWELL1 signaling is associated with impaired b-cell function in T2D. The objective of the current proposal is to delineate the mechanisms by which SWELL1 signaling regulates b-cell function, under basal conditions, and in the setting of Type 2 diabetes. Our central hypothesis is that SWELL1 regulates both glucose-stimulated insulin secretion and PI3K-AKT-mTOR signaling in b-cells to maintain systemic glycaemia, and that impaired SWELL1 signaling contributes to b-cell failure in Type 2 diabetes. The contribution of this proposal is significant because it explores the innovative concept the SWELL1 utilizes dual signaling domains (channel versus LRRD) to regulate b-cell function in health and T2D. Importantly, this proposal will also define the relationship between b-cell SWELL1 and T2D and test the notion that reduced SWELL1 signaling may drive impaired b-cell function in T2D. We propose the following two AIMs: AIM#1: Delineate the mechanism(s) of SWELL1-mediated regulation of excitation-secretion coupling. AIM#2: Dissect the molecular mechanisms of SWELL1 macro-complex regulation of AKT-mTOR signaling in b-cells. The contribution of this proposal is innovative because it delineates a novel SWELL1 signaling pathway that connects glucose-mediated b-cell swelling to b-cell depolarization and insulin-release - a form of b-cell swell- activation or “swell-secretion” coupling. This proposal will enhance our understanding of b-cell biology and help direct novel therapeutic approaches to b-cell failure in Type 2 diabetes. !

项目概要/摘要 据估计，四分之一的退伍军人患有糖尿病，而在退伍军人群体中，这主要是 2 型糖尿病 这种情况会导致心脏病、中风、视网膜病、肾病和神经病，所有这些疾病。 是我们退伍军人发病率和死亡率显着的一个原因，因此，了解其生物学。 糖尿病，发现调节 B 细胞功能的新分子并开发创新疗法 方法将对我们老龄化退伍军人群体的健康产生重大影响。 其特征是胰岛素敏感性的丧失，以及最终胰岛素分泌的相对丧失。 胰腺 b 细胞的胰岛素分泌是由 Ca2+ 通过电压门控流入触发的。 Ca2+ 通道 (VGCC) 触发胰岛素囊泡与 b 细胞质膜融合。 我们最近报道了 SWELL1 (LRRC8a)，一种富含亮氨酸重复序列的蛋白 家族，是 SWELL1 介导的 ICl,SWELL 所必需的，ICl,SWELL 在 b 细胞肿胀诱导时激活。 葡萄糖输入，这会产生有助于 VGCC 激活的去极化电流，从而调节 事实上，具有 SWELL1 缺陷的 β 细胞的小鼠表现出葡萄糖受损。 此外，我们发现两只小鼠的 ICl,SWELL 均减少。 以及 2 型糖尿病 (T2D) 背景下的人类表明 SWELL1 信号传导减少与之相关 T2D 中 b 细胞功能受损当前提案的目标是通过以下方式描述机制。 其中 SWELL1 信号在基础条件下和 2 型环境中调节 b 细胞功能 我们的中心假设是 SWELL1 调节葡萄糖刺激的胰岛素分泌和糖尿病。 b 细胞中的 PI3K-AKT-mTOR 信号传导维持全身血糖，并损害​​ SWELL1 信号传导导致 2 型糖尿病的 B 细胞衰竭。该提案的贡献是显着的。 因为它探索了创新概念，所以 SWELL1 利用双信号域（通道与 LRRD）来调节健康和 T2D 中的 b 细胞功能。重要的是，该提案还将定义这种关系。 b 细胞 SWELL1 和 T2D 之间的关系，并测试减少 SWELL1 信号传导可能驱动受损的 b 细胞的概念 我们提出以下两个目标： AIM#1：描述 SWELL1 介导的兴奋-分泌耦合调节机制。 AIM#2：剖析 SWELL1 宏复合物调控 AKT-mTOR 的分子机制 b 细胞中的信号传导。 该提案的贡献具有创新性，因为它描绘了一种新颖的 SWELL1 信号通路 将葡萄糖介导的 B 细胞肿胀与 B 细胞去极化和胰岛素释放（B 细胞肿胀的一种形式）联系起来 激活或“膨胀-分泌”耦合该提案将增强我们对 b 细胞生物学的理解并有助于。 直接治疗 2 型糖尿病 B 细胞衰竭的新方法。 ！