Role of NTS POMC neurons in energy homeostasis

描述(由申请人提供)： 肥胖是西方世界的一个主要健康问题，也是心血管疾病和糖尿病的主要诱因。肥胖的原因是多方面的。然而，它的严重性和早发性在儿童中的单基因突变的前阿片黑素皮质素(POMC)和Metanocortin-4受体基因突显了POMC系统在调节能量平衡的重要性。值得注意的是，POMC神经元的胞体只位于大脑的两个区域：下丘脑的弓状核(ARC)和延髓的孤束核(NTS)。由于任何使用黑素皮质素或阿片类药物的药物干预都会影响这两个区域的信号传递，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，尽管NTS接受内脏感觉输入，并与被认为是摄食中心的区域相互联系，但NTS中的POMC神经元在能量平衡中的作用仍不清楚。我推测这些NTS-POMC神经元是控制能量平衡的神经通路的重要组成部分，并能够将感觉传入和激素输入整合到NTS中。这项研究计划使用多学科方法来解决这一假说的关键方面。LOW实验室最近开发了转基因小鼠，其中POMC神经元通过EGFP进行鉴定，从而允许使用电生理和免疫细胞化学技术来检查这些POMC神经元在NTS通路中的位置。提出的特定目标将确定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。这项提议的一个重要方面是培训目标。Michael Anresen博士对其研究NTS神经元及其传入输入对其调节的独特设置的知识和经验对于使用电生理学方法描述NTS POMC神经元的这一提议至关重要。此外，我计划利用OHSU在这一领域的丰富经验和知识，扩大我在免疫细胞化学和追溯标记研究方面的培训，因为这些技术对我成为一名独立调查员的长期职业目标将是无价的。

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.