Ion channel regulation of pancreatic islet cell function

项目摘要/摘要 据估计，每4名退伍军人中就有1人患有糖尿病，在退伍军人中，这主要是2型 糖尿病。这种情况会导致心脏病、中风、视网膜病变、肾病和神经病变，所有这些 是导致退伍军人严重患病和死亡的一个原因。因此，了解生物的生物学 糖尿病，发现调节b细胞功能的新分子，开发创新的治疗方法 这些方法将对我们老年退伍军人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为特征，并最终导致胰岛素分泌的相对丧失。 胰腺B细胞。胰腺b细胞的胰岛素分泌是由电压门控的钙离子内流触发的。 钙通道(VGCC)触发胰岛素囊泡与b细胞质膜融合。 我们最近报道了富含亮氨酸重复序列中含有蛋白质的SWELL1(LRRC8a) 家族，是ICL所必需的，在β细胞中肿胀。SWELL1介导的ICL，Swell激活B细胞肿胀 葡萄糖输入，这产生有助于VGCC激活的去极化电流，从而调节 胰岛素分泌和全身性血糖。事实上，带有SWELL1缺陷β细胞的小鼠表现出血糖受损- 刺激胰岛素分泌和葡萄糖耐量减低。此外，我们发现ICL，Swell在两种小鼠中都有减少。 而人类在2型糖尿病(T2D)的背景下表明SWELL1信号的减少与 伴有T2D的B细胞功能受损。目前提案的目标是通过以下方式界定这些机制 在基础条件下和在类型2的设置中，哪个SWELL1信号调节b细胞功能 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PI3K-AKT-mTOR信号维持全身性血糖，并损害SWELL1 信号转导导致了2型糖尿病患者的b细胞衰竭。这项建议的贡献是巨大的。 因为它探索了创新的概念，SWELL1利用了双信令域(通道与 LRRD)来调节健康和T2D患者的B细胞功能。重要的是，这项提议还将定义两国关系 在b细胞SWELL1和T2D之间，并测试SWELL1信号减弱可能驱动受损的b细胞的概念 在T2D中的函数。我们提出以下两个目标： 目的#1：阐明SWELL1介导的兴奋-分泌偶联调节机制(S)。 目的#2：剖析SWELL1大分子复合体调控AKT-mTOR的分子机制 B细胞中的信号转导。 这一提议的贡献是创新的，因为它描绘了一条新的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“肿胀-分泌”耦合。这项建议将增进我们对b细胞生物学的了解，并有助于 2型糖尿病b细胞衰竭的直接新治疗方法。 好了！

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. !