G Protein signaling at the endosome

描述(申请人提供)：在大多数工业化国家，肥胖症的流行率正在上升，是心脏病和癌症等重大健康并发症的主要原因。问题的根源在于，当我们面对过量食物时，我们无法控制食物的摄入量。至关重要的是，我们要了解大脑的奖赏和动机回路如何调节食物摄入量，以及导致肥胖的功能障碍的本质。虽然研究已经确定下丘脑是外周代谢信号的关键媒介，但尚不清楚这种信号是如何转化为进食行为的。这项建议关注的是一种名为黑色素浓缩激素(MCH)的下丘脑神经肽。MCH产生于下丘脑外侧，这是一个历史上与奖赏行为相关的区域。此外，MCH受体在伏隔核表达，该区域也研究奖赏和药物成瘾。初步数据表明，MCH向伏隔核发出信号来调节摄食行为。用基因组和磷蛋白分析来阐明伏隔核内MCH受体信号的细胞和分子效应。拟议中的实验结果将阐明MCH在伏隔核中的作用机制，同时也有助于更好地从分子上解释神经肽如何调控复杂的动物行为，如食物摄取。

DESCRIPTION (provided by applicant): The prevalence of obesity is increasing in most industrialized nations and is a primary cause of significant health complications, such as heart disease and cancer. At the source of the problem is our inability to control food intake when presented with excess food. It is critical that we understand how reward and motivation circuits of the brain regulate food intake and the nature of the dysfunction that causes obesity. While research has identified the hypothalamus as a critical mediator of peripheral metabolic signals, it is not clear how this is converted into the act of eating. This proposal focuses on a hypothalamic neuropeptide called melanin-concentrating hormone (MCH). MCH is produced in the lateral hypothalamus, a region that has been historically associated with rewarding behavior. Moreover, the MCH receptor is expressed in the nucleus accumbens, a region also studies for reward and drug addiction. Preliminary data is presented to demonstrate that MCH signals to the nucleus accumbens to regulated feeding behavior. Experiments are proposed to elucidate the cellular and molecular effects of MCH receptor signaling in the nucleus accumbens using genomic and phosphoprotein analysis. The results from the proposed experiments will shed light on mechanisms of MCH action in the nucleus accumbens while also serving to provide a better molecular explanation of how neuropeptides regulate complex animal behaviors such as food intak.