Hypothalamic VMN neurons in the control of glucose homeostasis

下丘脑 VMN 神经元控制葡萄糖稳态

• 批准号: 8867520
• 负责人: THOMAS Harris MEEK
• 金额: $ 12.79万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867520
• 关键词: Ablation; Address; Affect; Animals; Anterior; Anterior Hypothalamus; Architecture; Area; Automobile Driving; Behavior; Beta Cell; Blood Glucose; Brain; Cell Nucleus; Characteristics; Collaborations; Continuing Education; Data; Development; Diabetes Mellitus; Diet; Doctor of Philosophy; Dose; Effectiveness; Electric Stimulation; Endocrinology; Ensure; Equilibrium; Fatty acid glycerol esters; Fellowship; Food Intake Regulation; Functional disorder; Glucagon; Glucose; Glucose Intolerance; Goals; Health; Hepatic; Histocytochemistry; Hyperglycemia; Hypoglycemia; Hypothalamic structure; Incidence; Insulin; Insulin-Dependent Diabetes Mellitus; Journals; Laboratories; Leptin; Leptin deficiency; Letters; Lifting; Manuscripts; Maps; Measures; Mediating; Mentors; Metabolic Diseases; Metabolism; Methods; Michigan; Microinjections; Modeling; Molecular Biology; Molecular Target; Mus; Neuraxis; Neurobiology; Neurons; Neurosciences; Neurosecretory Systems; Nutrient; Outcome Study; Pathology; Pathway interactions; Peripheral; Pharmacology; Physiological; Physiology; Plasma; Play; Prevalence; Publications; Qualifying; Regulation; Research; Research Scientist Award; Rhodopsin; Risk; Rodent Model; Role; SF1; Sampling; Scientist; Signal Transduction; Site; Streptozocin; Structure of terminal stria nuclei of preoptic region; Techniques; Technology; Testing; Toxin; Training; Universities; Viral; Virus; Washington; Work; base; behavior observation; blood glucose regulation; career; cell type; diabetic; energy balance; experience; glucose disposal; glucose metabolism; glucose production; glucose tolerance; glycemic control; hyperglucagonemia; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; meetings; member; novel; optogenetics; parabrachial nucleus; programs; promoter; recombinase; response; stem; targeted treatment; type I diabetic; ventromedial hypothalamic nucleus

DESCRIPTION (provided by applicant): This application delineates a 5-year program to provide the training toward the development of an independent academic research career in the study of neuron control of glucose homeostasis. The goal of this research program will be to determine brain mechanisms that govern normal physiology and pathophysiology of blood sugars in order to provide molecular targets for therapy. The candidate has been prepared for this pathway by completing a PhD degree involving the study of high-fat diet effects on voluntary activity, leptin signaling, and metabolic disease. Following his PhD, the candidate continued to gain new abilities working as a postdoctoral scientist with a type 1 diabetic model leading to the identification of the ventromedial nucleus of the hypothalamus (VMN) as a critical node requiring energy signals for normalization of diabetic hyperglycemia. The applicant has been very productive through both graduate and postdoctoral work contributing to 21 manuscripts to well respected journals, 8 of them first author. He has successfully competed for fellowships in the past and now seeks a Mentored Research Scientist Award to support ongoing efforts to harness the power of optogenetics to manipulate specific types of neurons to identify those required for glucose balance. Although the pursuit of novel, emergent areas of research entails an inherent degree of risk, this endeavor has already generated fruitful data and continues to provide a valuable training experience. The proposed research will be conducted in the laboratory of Dr. Michael Schwartz and Dr. Gregory Morton, both experts in the field of hypothalamic regulation of energy balance and glucose homeostasis, and will involve collaboration with a large group of experts in metabolism and glucose flux at the University of Washington and Vanderbilt (Dr. David Wasserman). It will be overseen by an expert mentoring committee with two members of the Endocrinology Division (Dr. Steven Kahn and Dr. Joshua Thaler) as well as an external advisor well respected for his research and mentoring capacity (Dr. Martin Myers, University of Michigan). The comprehensive training plan involves continued education in viral targeting techniques and methods for the determination of insulin-dependent and insulin-independent glucose disposal. The work will be presented at national meetings and through scientific publication. Both past and current work implicates the brain in the control of glucose homeostasis yet much about how this control occurs and the pathologies induced by its dysregulation remain unknown The goal of the current work is to identify neurocircuits that control blood glucose and to investigate how they mediate their effects. The application focuses on evidence that hypothalamic VMN neurons play a critical role to regulate glucose balance under physiological settings, and that activation of these neurons results in pathophysiological hyperglycemia and glucose intolerance. Using state-of-the-art optogenetics approaches with cre-dependent channel rhodopsin-expressing virus to exclusively target SF1 neurons within the VMN the preliminary data identify a subset of VMN neurons that, when activated, induce diabetes-range hyperglycemia in otherwise normal mice. This finding supports studies proposed in Specific Aim 1 to determine the mechanisms underlying the effect on glucose homeostasis of VMN neuron activation and its pathophysiological role in diabetic hyperglycemia. Two different approaches will be applied to understand how glucose control is changed, the euglycemic-hyperinsulinemic clamp and frequently sampled intravenous glucose tolerance test. Each method yields information regarding glucose homeostasis that is distinct, complementary, and ultimately required for a full understanding of study outcomes with the former providing evidence for insulin-dependent glucose regulation while the later measures insulin-independent glucose disposal. Additional preliminary data using optogenetics shows that upon activation of the SF1 neuronal projections to the aBNST glucose concentrations are again increased where photo-activation of other SF1 projection sites revealed no change. These findings identify the SF1→ aBDNF neuron projections as the first defined hypothalamic neurocircuit capable of driving hyperglycemia and provide a basis to continue characterizing this circuit and determine its relevance in insulin dependent diabetes as proposed in Specific Aim 2. The applicant's combination of expertise in molecular biology, histochemistry, pharmacology, and physiology of the neuronal regulation of food intake and glucose metabolism uniquely qualify him to receive a Mentored Research Scientist Award. With this support, he will address key questions in the field of neurobiology and metabolism, the answers to which will increase our understanding of how the brain regulates glucose homeostasis to establish the basis of an independent career.

描述（由应用程序提供）：本申请描述了一项为期5年的计划，以为开发独立的学术研究生涯的培训，以研究葡萄糖稳态的神经元控制。该研究计划的目的是确定血糖正常生理和病理生理学的大脑机制，以提供治疗的分子靶标。候选人是通过完成涉及对自愿活动，瘦素信号传导和代谢疾病的高脂饮食影响的研究来为该途径准备的。在他的博士学位后，候选人继续获得新的能力，成为一名博士后科学家，具有1型糖尿病模型，从而鉴定出下丘脑（VMN）的腹侧核us，这是一个关键节点，这是一个关键节点，该关键节点需要能量信号，以归一化糖尿病性高血糖的范围。该应用程序通过研究生和博士后工作非常有效，为21种备受推崇的期刊（其中8个都是第一作者）的手稿。过去，他成功地争夺了奖学金，现在寻求指导的研究科学家奖，以支持持续的努力利用光遗传学操纵特定类型的神经元以识别葡萄糖平衡所需的力量。尽管对新颖，新兴研究领域的追求需要继承的风险，但这项工作已经产生了富有成果的数据，并继续提供宝贵的培训经验。拟议的研究将在迈克尔·施瓦茨（Michael Schwartz）博士和格雷戈里·莫顿（Gregory Morton）博士的实验室中进行，这两位专家是下丘脑对能量平衡和葡萄糖稳态的调节领域的专家，并将与华盛顿大学和范德比尔特大学（David Br. David wasserman wassmerman wasserman wasserman wasserman wasserman of Sebolismist and Glux Flux consecortion conssoration consssonce。这将由一个专家指导委员会监督，由内分泌科（Steven Kahn博士和Joshua Thaler博士）的两名成员以及一位对其研究和心理能力受到尊重的外部顾问（密歇根大学Martin Myers博士）。全面的培训计划涉及对病毒靶向技术的持续教育以及确定胰岛素依赖性和胰岛素独立的葡萄糖处置的方法。这项工作将在国家聚会和科学出版物上介绍。过去和当前的工作都在控制葡萄糖稳态方面实现了大脑，但有关这种控制的发生方式，其失调引起的病理仍然尚不清楚，目前工作的目的是识别控制血糖并研究其介导其作用的神经电路。该应用集中在证据表明下丘脑VMN神经元在身体环境下调节葡萄糖平衡的关键作用，并且这些神经元的激活导致病理生理高血糖和葡萄糖intlerance。使用与CRE依赖性通道表达病毒的最先进的光遗传学方法，可以专门靶向VMN中的SF1神经元，初步数据确定了VMN神经元的子集，当激活后，这些神经元在其他正常小鼠中诱导糖尿病 - 范围高血糖。该发现支持在特定目标1中提出的研究，以确定对VMN神经元激活葡萄糖稳态的影响的基础机制及其在糖尿病高血糖中的病理生理作用。将采用两种不同的方法来了解如何改变葡萄糖的控制，尿性糖纤维素夹和经常采样的静脉葡萄糖耐受性测试。每种方法都会产生有关葡萄糖稳态的信息，这些信息是不同，完整且最终需要的，以充分了解研究结果，而前者为胰岛素依赖性葡萄糖调节提供了证据，而后来的措施胰岛素独立于葡萄糖处置。使用光遗传学的其他初步数据表明，在激活SF1神经元投影后，向AbnST葡萄糖浓度再次增加，而其他SF1投影位点的光激活显示没有变化。这些发现确定了SF1→ABDNF神经元预测是能够驱动高血糖的第一个定义的下丘脑神经循环，并提供了继续表征该电路的基础，并确定其在胰岛素依赖性糖尿病中的相关性，如特定的目标2。葡萄糖代谢独特地使他获得了指导的研究科学家奖。在这种支持下，他将解决神经生物学和代谢领域的关键问题，这些答案将增加我们对大脑如何调节葡萄糖体内稳态以建立独立职业的基础的理解。