Role of NTS POMC neurons in energy homeostasis

NTS POMC 神经元在能量稳态中的作用

• 批准号: 7000300
• 负责人: Suzanne M Appleyard
• 金额: $ 9.99万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7000300
• 关键词: bioenergetics; cardiovascular disorder; diabetes mellitus; electrophysiology; gene mutation; genetically modified animals; homeostasis; immunocytochemistry; laboratory mouse; neurons; neurotransmitters; obesity; polymerase chain reaction; proopiomelanocortin; solitary tract nucleus

DESCRIPTION (provided by applicant): Obesity is a major health problem in the Western world and is a leading contributor to cardiovascular disease and diabetes mellitus. The causes of obesity are multifactorial. However, its severity and early onset in children with monogenic mutations in the proopiomelanocortin (POMC) and metanocortin-4 receptor genes highlight the importance of the POMC system in the regulation of energy balance. Remarkably, the cell bodies of POMC neurons are located in only two regions of the brain: the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the solitary tract (NTS) in the medulla. As any pharmacological intervention using either melanocortin or opioid drugs will affect the signaling from both regions, it is critical to determine the function of the NTS-POMC neurons for rational predictions concerning the long-term consequences of drug therapy aimed at these targets. However, although the NTS receives visceral sensory inputs and is interconnected with regions proposed to act as feeding centers, the role of the POMC neurons in the NTS in energy homeostasis remains unknown. I hypothesize that these NTS-POMC neurons are a vital component of neural pathways that control energy homeostasis and are capable of integrating the sensory afferent and hormonal input into the NTS. This research plan uses a multi-disciplinary approach to address key aspects of this hypothesis. The Low lab has recently developed transgenic mice in which the POMC neurons are identified by EGFP, allowing the examination of the rote of these POMC neurons in the NTS pathways, using both electrophysiological and immunocytochemical techniques. The proposed specific aims will identify neuroanatomic, neurochemical, regulatory, and molecular properties of NTS-POMC neurons. In addition, I plan to ablate the NTS-POMC neurons to directly determine if they are important for energy balance. An important aspect of this proposal are the training goals. Dr. Michael Andresen's knowledge and experience with his unique set up for studying NTS neurons and their regulation by afferent inputs are critical for this proposal to characterize the NTS POMC neurons using electrophysiological approaches. Additionally, I plan to expand my training in immunocytochemicat and retrolabeling studies by utilizing the extensive experience and knowledge in this area available at OHSU, as these techniques will be invaluable for my long-term career goal of becoming an independent investigator.

描述（由申请人提供）： 肥胖是西方世界的一个主要健康问题，是心血管疾病和糖尿病的主要原因。肥胖的原因是多因素的。然而，阿黑皮素原 (POMC) 和变皮质素 4 受体基因单基因突变儿童的严重性和早发性凸显了 POMC 系统在能量平衡调节中的重要性。值得注意的是，POMC 神经元的细胞体仅位于大脑的两个区域：下丘脑弓状核 (ARC) 和延髓中的孤束核 (NTS)。由于使用黑皮质素或阿片类药物的任何药物干预都会影响这两个区域的信号传导，因此确定 NTS-POMC 神经元的功能对于合理预测针对这些目标的药物治疗的长期后果至关重要。然而，尽管 NTS 接收内脏感觉输入并与提议充当喂养中心的区域互连，但 NTS 中的 POMC 神经元在能量稳态中的作用仍然未知。我假设这些 NTS-POMC 神经元是控制能量稳态的神经通路的重要组成部分，并且能够将感觉传入和激素输入整合到 NTS 中。该研究计划采用多学科方法来解决该假设的关键方面。 Low 实验室最近开发了转基因小鼠，其中的 POMC 神经元由 EGFP 识别，从而可以使用电生理学和免疫细胞化学技术来检查 NTS 通路中这些 POMC 神经元的死记硬背。拟议的具体目标将确定 NTS-POMC 神经元的神经解剖学、神经化学、调节和分子特性。此外，我计划消融 NTS-POMC 神经元，以直接确定它们对能量平衡是否重要。该提案的一个重要方面是培训目标。 Michael Andresen 博士的知识和经验以及他研究 NTS 神经元及其传入输入调节的独特设置对于使用电生理学方法表征 NTS POMC 神经元的提议至关重要。此外，我计划利用 OHSU 在该领域的丰富经验和知识来扩展我在免疫细胞化学和逆标记研究方面的培训，因为这些技术对于我成为独立研究者的长期职业目标将非常宝贵。