TALK-1 channels as a novel target to modulate basal insulin secretion and obesity

 描述（由申请人提供）：本提案中概述的培训计划侧重于阐明双孔结构域K+通道TALK-1调节胰岛激素分泌的分子机制，并定义这些过程如何有助于维持葡萄糖稳态。我们的初步研究结果表明，TALK-1通道参与高血糖症和肥胖症的发病机制;然而，导致这种影响的潜在机制尚不清楚。重要的是，TALK-1的非同义多态性与2型糖尿病（T2 DM）易感性增加有关。我们最近发现，β细胞TALK-1通道限制基础和第2时相胰岛素分泌，并有助于响应于高脂饮食（HFD）的慢性代谢应激的空腹高血糖症的发展。虽然这些观察结果表明TALK- 1通道在维持葡萄糖稳态中起关键作用，但关于TALK-1通道的调节或生理作用知之甚少。这是确定TALK- 1通道如何影响T2 DM发病机制的主要障碍。我们强有力的初步研究结果表明，在慢性代谢应激的背景下，TALK-1通道对基础胰岛素分泌的调节影响肝脏胰岛素敏感性。此外，我们发现，小鼠缺乏 保护TALK-1通道免受HFD诱导的肥胖，在置于HFD上后不久，相对于对照小鼠明显减轻体重和肥胖。我们的初步数据显示，这可能是由喂食HFD的TALK-1 KO小鼠的食物摄入量减少引起的。本文的目的是确定TALK-1通道调节胰岛激素分泌如何影响代谢稳态。我们假设TALK-1通道依赖性调节胰岛激素分泌控制肝脏葡萄糖的产生和食物摄入。我将通过体外研究转基因小鼠和人胰岛细胞对促分泌素的反应来确定TALK-1通道调节胰岛激素分泌的机制，从而验证中心假设（目的1）。这些发现将扩展到TALK-1通道如何促进体内高血糖症和肥胖症的发展的详细研究（目的2）。这项研究的成功完成将促进我们对调节胰岛细胞功能的基本机制的理解。此外，阐明TALK-1通道对饮食诱导的肥胖症和高血糖症的影响将极大地扩展对TALK- 1对T2 DM发病机制的潜在作用的理解。通过这项奖学金申请，我将开发1）胰岛TALK-1通道的调节和生理功能的新的理解，2）我作为一个独立的研究者专注于肠内分泌细胞功能的潜力。这些培训目标将通过详细的研究计划，具有拟议研究设计专业知识的特别合格的导师以及范德比尔特大学提供的优秀设施和培训资源来实现。

 DESCRIPTION (provided by applicant): The training plan outlined in this proposal focuses on elucidating the molecular mechanisms underlying modulation of islet hormone secretion by the two-pore domain K+ channel TALK-1, and defining how these processes contribute to maintenance of glucose homeostasis. Our preliminary findings indicate that TALK-1 channels participate in the pathogenesis of hyperglycemia and obesity; however, the underlying mechanisms contributing to this effect are unknown. Importantly, a non-synonymous polymorphism in TALK-1 is linked to increased type-2 diabetes mellitus (T2DM) susceptibility. We have recently shown that β-cell TALK-1 channels limit basal and 2nd-phase insulin secretion, and contribute to the development of fasting hyperglycemia in response to the chronic metabolic stress of a high-fat diet (HFD). While these observations indicate that TALK- 1 channels serve a critical role in the maintenance of glucose homeostasis, little else is known about the regulation or physiological roles of TALK-1 channels. This presents a major obstacle to determining how TALK- 1 channels impact the pathogenesis of T2DM. Our strong preliminary findings indicate that TALK-1 channel modulation of basal insulin secretion impacts hepatic insulin sensitivity in the context of chronic metabolic stress. Moreover, we find that mice lacking TALK-1 channels are protected from HFD-induced obesity, with reduced body weight and adiposity relative to control mice evident shortly after being placed on a HFD. Our preliminary data show that this is likely caused by the reduced food intake of TALK-1 KO mice fed a HFD. The goal here is to define how TALK-1 channel modulation of islet hormone secretion impacts metabolic homeostasis. We hypothesize that TALK-1 channel-dependent modulation of islet hormone secretion controls hepatic glucose production and food intake. I will test the central hypothesis by determining the mechanisms by which TALK-1 channels modulate islet hormone secretion through in vitro studies of transgenic mouse and human islet cell function in response to secretagogues (Aim 1). These findings will be extended to detailed studies of how TALK-1 channels contribute to the development of hyperglycemia and obesity in vivo (Aim 2). Successful completion of the proposed research will advance our understanding of the fundamental mechanisms regulating islet cell function. Moreover, elucidating the influence of TALK-1 channels on diet- induced obesity and hyperglycemia will greatly expand comprehension of the mechanisms underlying TALK- 1's contributions to the pathogenesis of T2DM. Through this fellowship application, I will develop 1) a novel understanding of the regulation and physiological functions of islet TALK-1 channels, and 2) my potential as an independent investigator focused on enteroendocrine cell function. These training goals will be facilitated by the detailed research plan, the exceptionally qualified mentors with expertise in th proposed study design, and the outstanding facilities and training resources available through Vanderbilt University.