Role of NTS POMC neurons in energy homeostasis

描述（由申请人提供）： 肥胖是西方世界的主要健康问题，并且是心血管疾病和糖尿病的主要贡献者。肥胖的原因是多方面的。然而，它的严重性和早期发作的儿童与单基因突变的阿黑皮素原（POMC）和metanocortin-4受体基因突出的重要性，POMC系统在调节能量平衡。值得注意的是，POMC神经元的胞体仅位于大脑的两个区域：下丘脑弓状核（ARC）和延髓孤束核（NTS）。由于使用黑皮质素或阿片类药物的任何药理学干预都会影响来自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靶点的药物治疗的长期后果至关重要。然而，虽然NTS接收内脏感觉输入，并与建议作为摄食中心的区域相互连接，但NTS中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。本研究计划采用多学科方法来解决这一假设的关键方面。Low实验室最近开发了转基因小鼠，其中POMC神经元通过EGFP鉴定，允许使用电生理学和免疫细胞化学技术检查这些POMC神经元在NTS通路中的作用。提出的具体目标将确定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。这项建议的一个重要方面是培训目标。Michael Andresen博士在研究NTS神经元及其通过传入输入调节的独特设置方面的知识和经验对于使用电生理方法表征NTS POMC神经元的建议至关重要。此外，我计划通过利用OHSU在该领域的丰富经验和知识来扩大我在免疫细胞化学和逆转录标记研究方面的培训，因为这些技术对我成为独立研究者的长期职业目标非常宝贵。

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.