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: 10664931
• 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/10664931
• 关键词: Ablation; Adipose tissue; Aging; Anions; Attention; B-Lymphocytes; Beta Cell; Biology; C-terminal; Cadaver; Cell Proliferation; 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; Metabolism; Microscopy; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; PIK3CG gene; 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; candidate validation; cell growth; experimental study; gain of function; in vivo; innovation; insight; insulin secretion; insulin sensitivity; islet; knowledge base; loss of function; 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. !

项目摘要/摘要 据估计，有4位退伍军人患有糖尿病，在退伍军人人口中，这主要是2型 糖尿病。这种疾病驱动心脏病，中风，视网膜病，肾病和神经病，所有这些 这是我们退伍军人中发病率和死亡率显着的原因。因此，了解 糖尿病，发现调节B细胞功能并发展创新疗法的新分子 方法将对我们老化的退伍军人人口的健康产生重大影响。 2型糖尿病是 以胰岛素敏感性的丧失，最终是胰岛素分泌的相对损失的特征 胰腺B细胞。胰腺B细胞的胰岛素分泌是由Ca2+影响通过电压门控触发的 Ca2+通道（VGCC）与B细胞质膜触发胰岛素蔬菜融合。 我们最近报道说Swell1（LRRC8A），含有蛋白的富含亮氨酸的成员 家族是ICL所必需的，β细胞膨胀。 Swell1介导的ICL，在B细胞肿胀引起的B细胞肿胀时激活 葡萄糖导入，这会产生促进VGCC激活的分裂电流，从而调节 胰岛素分泌和系统性血糖。实际上，患有Swell1缺乏β细胞暴露于葡萄糖的小鼠暴露于 刺激的胰岛素分泌和葡萄糖interance。此外，我们发现两只鼠标中的ICL，膨胀均减少 在2型糖尿病（T2D）的背景下，人类表明SWELL1信号的减少是相关的 T2D中的B细胞功能受损。当前建议的目的是通过 在基本条件下，在类型2的情况下，哪些信号传导调节B细胞函数 糖尿病。我们的中心假设是Swell1调节葡萄糖刺激的胰岛素分泌和 B细胞中的PI3K-AKT-MTOR信号传导以维持全身性高血症，而Swell1受损 信号导致2型糖尿病的B细胞衰竭。该提议的贡献很重要 因为它探索了创新概念，所以Swell1使用了双信号域（通道与） LRRD）调节健康和T2D的B细胞功能。重要的是，该建议还将定义关系 在B细胞swell1和t2d之间，并测试降低的Swell1信号传导可能会驱动受损的B细胞的观念 T2D的功能。我们提出以下两个目标： 目的＃1：描述Swell1介导的兴奋 - 分泌耦合调节的机制。 AIM＃2：剖析Akt-Mtor的Swell1宏观复合调节的分子机制 在B细胞中发出信号。 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 连接葡萄糖介导的B细胞肿胀与B细胞沉积和胰岛素释放 - 一种B细胞膨胀形式 激活或“膨胀分泌”耦合。该建议将增强我们对B细胞生物学的理解并帮助 2型糖尿病中B细胞衰竭的直接新型热方法。 呢

项目成果

The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function.

• DOI: 10.7554/elife.61313
• 发表时间: 2021-02-25
• 期刊: eLife
• 影响因子: 7.7
• 作者: Alghanem AF;Abello J;Maurer JM;Kumar A;Ta CM;Gunasekar SK;Fatima U;Kang C;Xie L;Adeola O;Riker M;Elliot-Hudson M;Minerath RA;Grueter CE;Mullins RF;Stratman AN;Sah R
• 通讯作者: Sah R