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，约占美国诊断性糖尿病病例的90-95％。我们在此提案中的目标是阐明一种新型的葡萄糖调节中性机制，该机制可以显着提高我们对T2D发病机理的理解。传统上被视为心血管调节系统的脑肾素 - 血管紧张素系统（RAS）最近已成为代谢和能量预期信号系统的关键部分。但是，大脑RA是否在血糖调节中起作用，如果是的，则通过什么信号传导机制构成了我们所知的主要差距。 RAS的关键成分（Pro）肾素受体（PRR）介导了血管紧张素II（ANG II）的形成 - RAS的主要生物活性肽 - 和中枢神经系统（CNS）中的ANG II独立信号传导。在该提案中，我们提供了重要的初步数据，该数据支持以下概念：在下丘脑的旁腔内核核苷中，酪氨酸羟化酶（Th）阳性神经元中的PRR称为THPVN神经元，称为THPVN神经元，是GLACEMIA的新型调节剂。根据该提议，试图发现THPVN神经元和PRR在调节血糖中的新作用，并研究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，并且该神经元途径的激活在HFD消耗期间有助于葡萄糖代谢障碍。为了检验这一假设，我们将使用一种多学科方法，该方法结合了体内遥测葡萄糖监测，使用Dreadds（由设计师药物专门激活的设计师受体），体外电生理学的化学生成技术，以及在甲状腺梗核核中的TH神经元特异性靶向。拟议项目的成功完成将提高我们对葡萄糖稳态自主调节中脑PRR和THPVN神经元的新作用和机制的理解，并为T2D提供了潜在的治疗靶点。