Neural mechanisms regulating glucose homeostasis

修改后的项目摘要/摘要部分 2型糖尿病(T2D)是人类糖尿病的主要形式，约占美国糖尿病确诊病例的90%-95%。我们在这个建议中的目标是阐明一种新的血糖调节的神经机制，从而显著促进我们对T2D发病机制的理解。脑肾素-血管紧张素系统(RAS)，传统上被视为心血管调节系统，最近已成为代谢和能量消耗信号系统的重要组成部分。然而，大脑RAS是否在血糖调节中发挥作用，如果是，通过什么信号机制，构成了我们知识的主要空白。肾素受体(PRR)是RAS的重要组成部分，在中枢神经系统(CNS)调节血管紧张素II(Ang II)的形成和Ang II非依赖性信号的形成。在这个方案中，我们提供了重要的初步数据，支持下丘脑室旁核酪氨酸羟化酶(TH)阳性神经元中的PRR是一种新的血糖调节器的概念。因此，这一提议试图揭示THPVN神经元和PRR在血糖调节中的新作用，并研究其潜在的分子和突触机制。我们的中心假设是，THPVN神经元中的PRR信号驱动自主神经反应，从而破坏葡萄糖稳态，而这一神经通路的激活有助于在摄入HFD时造成葡萄糖代谢障碍。为了验证这一假设，我们将使用一种多学科方法，结合体内远程血糖监测、使用DREADDS(由设计药物独家激活的设计者受体)的化学发生技术、体外电生理学和下丘脑室旁核TH神经元特异性靶向。该项目的成功完成将促进我们对大脑PRR和THPVN神经元在葡萄糖稳态自主神经调节中的新作用和新机制的理解，并为T2D提供潜在的治疗靶点。

Modified Project Summary/Abstract Section Type 2 diabetes mellitus (T2D) is the major form of human diabetes, accounting for approximately 90–95% of diagnosed diabetes cases in the United States. Our goal in this proposal is to elucidate a novel neural mechanism of glucose regulation that could significantly advance our understanding of the pathogenesis of T2D. The brain renin-angiotensin system (RAS), traditionally viewed as a cardiovascular regulatory system, has recently emerged as a critical part of metabolic and energy-expenditure signaling systems. However, whether the brain RAS play a role in glycemia regulation, and if so, via what signaling mechanisms, constitute major gaps in our knowledge. The (pro)renin receptor (PRR), a key component of the RAS, mediates both formation of angiotensin II (Ang II) – a major bioactive peptide of the RAS – and Ang II-independent signaling in the central nervous system (CNS). In this proposal, we provide important preliminary data supporting the concept that the PRR in tyrosine hydroxylase (TH)-positive neurons in the paraventricular nucleus of the hypothalamus, termed THPVN neurons, is a novel modulator of glycemia. Accordingly, this proposal seeks to uncover a novel role of THPVN neurons and the PRR in the regulation of glycemia and investigate the underlying molecular and synaptic mechanisms. Our central hypothesis is that that PRR signaling in THPVN neurons drives autonomic responses that impair glucose homeostasis, and that activation of this neural pathway contributes to glucose metabolic impairment during HFD consumption. To test this hypothesis, we will use a multidisciplinary approach combining in vivo telemetric glucose monitoring, chemogenic techniques employing DREADDs (designer receptor exclusively activated by designer drugs), in vitro electrophysiology, and TH neuron-specific targeting in the paraventricular nucleus of the hypothalamus. Successful completion of the proposed project will advance our understanding of a novel role and mechanisms of the brain PRR and THPVN neurons in the autonomic regulation of glucose homeostasis and provide a potential therapeutic target for T2D.