Neural mechanisms regulating glucose homeostasis

调节葡萄糖稳态的神经机制

• 批准号: 10634249
• 负责人: Yumei Feng Earley
• 金额: $ 56.34万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634249
• 关键词: Accounting; Address; Agreement; Angiotensin II; Area; Autonomic nervous system; Body Weight; Brain; Brain region; Cardiovascular system; Central Nervous System; Conscious; Consumption; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Eating; Electrophysiology (science); Energy Metabolism; Future; Genetic; Glucose; Goals; High Fat Diet; Homeostasis; Human; Hypothalamic structure; Impairment; In Vitro; Inactive Renin; Insulin; Investigation; Knowledge; Ligands; Liver; Mediating; Metabolic; Metabolic Control; Molecular; Monitor; Mus; Nervous System control; Neural Pathways; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Peptides; Physiological; Plasma; Play; Regulation; Renin; Renin-Angiotensin System; Reporting; Research; Role; Signal Transduction; Slice; Synapses; System; Techniques; Telemetry; Testing; Tissues; Tyrosine 3-Monooxygenase; United States; blood glucose regulation; design; designer receptors exclusively activated by designer drugs; diabetic; feeding; glucose disposal; glucose metabolism; glucose monitor; improved; in vivo; insight; insulin secretion; insulin sensitivity; interdisciplinary approach; member; metabolic phenotype; neural; neuromechanism; novel; novel therapeutics; paraventricular nucleus; promoter; receptor; response; therapeutic target

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.

修改项目摘要/摘要部分 2型糖尿病（T2 D）是人类糖尿病的主要形式，占美国诊断糖尿病病例的约90-95%。我们的目标是阐明一种新的葡萄糖调节的神经机制，可以显着提高我们对T2 D发病机制的理解。传统上被认为是心血管调节系统的脑肾素-血管紧张素系统（RAS）最近成为代谢和能量消耗信号系统的关键部分。然而，大脑RAS是否在神经元调控中发挥作用，如果是的话，通过什么样的信号传导机制，构成了我们知识的主要空白。肾素受体（PRR）是RAS的关键组分，在中枢神经系统（CNS）中介导血管紧张素II（Ang II）（RAS的主要生物活性肽）和Ang II非依赖性信号传导的形成。在这个建议中，我们提供了重要的初步数据支持的概念，PRR酪氨酸羟化酶（TH）阳性神经元在室旁核的下丘脑，被称为THPVN神经元，是一种新的调制器。因此，本研究试图揭示THPVN神经元和PRR在调节神经元兴奋性中的新作用，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信号传导驱动损害葡萄糖稳态的自主反应，并且该神经通路的激活有助于HFD消耗期间的葡萄糖代谢损害。为了验证这一假设，我们将使用一种多学科的方法，结合体内遥测葡萄糖监测，采用DREADD（设计师受体专门激活的设计师药物），在体外电生理学，TH神经元特异性靶向室旁核的下丘脑的化学技术。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调节中的新作用和机制的理解，并为T2 D提供潜在的治疗靶点。