Identification of the central localization and regulation of the Prokineticin 1 Receptor, a novel target for the treatment of obesity

项目摘要 前动力蛋白受体1（ProKR 1或PKR 1）是一种研究非常不足的GPCR，它有效地控制食物摄入 能量消耗和伤害感受。PKR 1刺激导致食物摄入量的有效减少和 能量消耗PKR 1的缺失导致严重肥胖和肥胖增加。因此，这是一个重要的 治疗肥胖症的新靶点。虽然这项建议将不会集中在PKR 1的这一方面， 在生理学上，PKR 1的外周抑制已显示降低伤害感受，因此，配体 对于PKR 1来说，它代表了阿片类药物治疗疼痛的一种有前途的替代品。在这个项目中，我们将重点关注 PKR 1在能量平衡控制中的作用。我们建议使用创新的小鼠模型， 开发并验证了精确绘制PKR 1在大脑中的分布。下丘脑是 能量稳态调节的主要中心，我们将确定神经元内的人口 下丘脑表达PKR 1。我们之前已经证明黑皮质素受体 辅助蛋白2（MRAP 2）是PKR 1的重要调节因子。为此，我们还将进行体内测试， 离体，MRAP 2如何调节神经元中PKR 1的运输和信号传导，以及PKR 1/MRAP 2复合物如何 通过食物摄入和禁食来调节。这些研究的结果将在很大程度上提高我们对 PKR 1的作用及其通过能量稳态和MRAP 2的调节。他们还将进一步展示 PKR 1作为肥胖症治疗新靶点的价值。

PROJECT SUMMARY The Prokineticin Receptor 1 (ProKR1 or PKR1) is a vastly understudied GPCR that potently controls food intake energy expenditure and nociception. PKR1 stimulation causes a potent decrease in food intake and increase in energy expenditure. Deletion of PKR1 causes severe obesity and increased adiposity. As such it is an important novel target for the treatment of obesity. While this proposal will not be focusing on this aspect of PKR1 physiology, peripheral inhibition of PKR1 has been shown to decrease nociception and consequently, ligands for PKR1 represent a promising alternative to opioids for the treatment of pain. In this project we will focus on the role of PKR1 in the control of energy homeostasis. We propose to use innovative mouse models that we developed and validated to accurately map the distribution of PKR1 in the brain. The hypothalamus being the main center of regulation of energy homeostasis, we will identify the population of neurons within the hypothalamus that expresses PKR1. We have previously demonstrated that the Melanocortin Receptor Accessory Protein 2 (MRAP2) is an important regulator of PKR1. For this reason, we will also test in-vivo and ex-vivo, how MRAP2 regulates PKR1 trafficking and signaling in neurons and how the PKR1/MRAP2 complex is regulated by food intake and fasting. Results from those studies will largely improve our understanding of the roles of PKR1 and its regulation by energy homeostasis and MRAP2. They will also further demonstrate the value of PKR1 as a new target for the treatment of obesity.