The role of vagal afferent neurons in regulating feeding behavior

描述（由申请人提供）：长期以来已知迷走神经在调节食物摄入中发挥作用。迷走神经传入通路感知肠道响应营养提示释放的激素，并将这些信号传递给脑干。我们最近证明，迷走神经传入神经元（货车）可以整合这些信号，并改变重要的感觉和信号的受体和神经肽递质的表达，以修改进食行为。在肥胖症中，货车中关键受体对其配体的敏感性降低，导致这些神经元的神经化学表型发生变化。不幸的是，该领域目前可用的技术不允许在体内操纵这些神经元，以确定这些蛋白质对摄食行为的功能作用。该提案的总体目标是确定迷走神经在调节摄食行为中的作用，特别关注了解迷走神经传入信号的失调如何导致饮食诱导的肥胖症中的摄食过多和体重增加。为了实现这一目标，我们提出1）确定神经肽递质可卡因和安非他明调节转录物（CART）和黑色素浓缩激素（MCH）从货车释放到脑干中在正常生理条件下调节进食行为中的作用以及它们在饮食诱导的肥胖症进展中的作用，2）VA中的瘦素抵抗对肥胖症进展的作用，以及3）使用针对MCH和瘦素受体下游效应物早期生长反应1（EGR-1）的干预研究来预防饮食诱导的肥胖症的发作。该提案的一个关键组成部分涉及开发一种新的体内RNAi方法来靶向货车表达的蛋白质。这项研究计划的预期成果是开发一种新的体内RNAi方法来靶向货车表达的蛋白质，并证明这种技术可以作为肥胖症的治疗工具以及阐明货车作用的研究工具。此外，成功完成将证明货车在食欲过盛和体重增加的发展中的重要作用;从而鉴定用于治疗肥胖的新的特异性分子靶点。

DESCRIPTION (provided by applicant): The vagus nerve has long been known to play a role in the regulation of food intake. The vagal afferent pathway senses hormones released from the gut in response to nutritional cues and relays these signals to the brain stem. We have recently demonstrated that vagal afferent neurons (VAN) can integrate these signals and alter expression of receptors and neuropeptide transmitters important in sensing and signalling, to modify feeding behavior. In obesity, the sensitivity of key receptors to their ligands are reduced in VAN, resulting in changes in the neurochemical phenotype of these neurons. Unfortunately the techniques currently available in the field do not allow manipulations of these neurons in vivo to determine the functional role of these proteins on feeding behavior. The overarching goal of this proposal will be to determine the role of the vagus nerve in regulating feeding behaviour with specific focus on understanding how dysregulation of vagal afferent signaling leads to the development of hyperphagia and weight gain in diet induced obesity. To achieve this goal we propose to 1) determine the role of the neuropeptide transmitters cocaine and amphetamine regulated transcript (CART), and melanin concentrating hormone (MCH) released from VAN into the brain stem in the regulation of feeding behavior under normal physiological conditions and their role in the progression of diet induced obesity, 2) the effect of leptin resistance in VA on the progression of obesity, and 3) to use an intervention study targeting MCH and the leptin receptor downstream effector early growth response 1 (EGR-1) to prevent the onset of diet induced obesity. A key component of this proposal involves the development of a novel in vivo RNAi approach to target proteins expressed by VAN. The expected outcomes of this research proposal are to develop a novel in vivo RNAi approach to target proteins expressed by VAN and to demonstrate that this technique could be applied as a therapeutic tool in obesity as well as a research tool to elucidate the role of VAN. In addition, successful completion would demonstrate an important role for VAN in the development hyperphagia and weight gain; thereby identifying novel specific molecular targets for the treatment of obesity.