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，约占美国诊断糖尿病病例的 90-95%。我们本提案的目标是阐明一种可以显着促进血糖调节的新型神经机制。我们对 T2D 发病机制的理解。传统上被视为心血管调节系统的大脑肾素-血管紧张素系统 (RAS) 最近已成为代谢和能量消耗信号系统的关键部分。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。 肾素原受体 (PRR) 是 RAS 的关键组成部分，介导血管紧张素 II 的形成。 (Ang II) – RAS 的主要生物活性肽 – 以及中枢神经系统 (CNS) 中的 Ang II 独立信号传导 在本提案中，我们提供了重要的初步数据，支持酪氨酸羟化酶中的 PRR 这一概念。下丘脑室旁核中的 (TH) 阳性神经元，称为 THPVN 神经元，是一种新型血糖调节剂。因此，本提案旨在揭示 THPVN 神经元和 PRR 在血糖调节中的新作用，并研究其潜在作用。我们的中心假设是，THPVN 神经元中的 PRR 信号传导会损害葡萄糖稳态，并且该神经通路的激活会导致葡萄糖代谢损伤。为了检验这一假设，我们将采用多学科方法，结合体内遥测血糖监测、采用 DREADD（专门由设计药物激活的设计受体）的化学技术、体外电生理学和室旁核中的 TH 神经元特异性靶向。该项目的成功完成将增进我们对大脑 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，并为下丘脑提供潜在的治疗靶点。 T2D。