The role of vagal afferent neurons in regulating feeding behavior

描述(由申请人提供)：迷走神经在食物摄入量的调节中起着重要作用。迷走神经传入通路感知肠道释放的荷尔蒙，对营养信号做出反应，并将这些信号传递给脑干。我们最近证实，迷走神经传入神经元(VAN)可以整合这些信号，改变感觉和信号传递中重要的受体和神经肽递质的表达，从而改变摄食行为。在肥胖中，VAN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，目前该领域可用的技术不允许在体内操纵这些神经元来确定这些蛋白质在摄食行为中的功能作用。这项提案的首要目标将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是如何导致饮食诱导肥胖的吞噬过度和体重增加的。为了实现这一目标，我们建议1)确定从VAN释放到脑干的可卡因和安非他明调节转录本(CART)和黑色素浓缩激素(MCH)在调节正常生理条件下的摄食行为中的作用及其在饮食诱导肥胖进展中的作用，2)VA中瘦素抵抗对肥胖进展的影响，以及3)使用针对MCH和瘦素受体下游效应因子早期生长反应1(EGR-1)的干预性研究来预防饮食诱导肥胖的发生。这项建议的一个关键组成部分涉及到开发一种新的体内RNAi方法来处理VAN表达的靶蛋白。这项研究的预期结果是开发一种新的体内RNAi方法来检测VAN表达的靶蛋白，并证明该技术可以作为肥胖症的治疗工具以及阐明VAN作用的研究工具。此外，VAN的成功完成将证明VAN在促进过度吞噬和体重增加方面发挥重要作用，从而确定治疗肥胖症的新的特定分子靶点。

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.