Neuronal GPR149 and energy homeostasis

项目总结/摘要 肥胖症和包括糖尿病在内的相关疾病的发病率继续上升。慢性过度 营养是普遍的，这有深刻的代谢影响，包括导致增加全身炎症 并改变了肝脏葡萄糖和脂质的产生。能量的分子机制研究 平衡对于制定新的预防策略，诊断测试和治疗慢性 代谢性疾病，如肥胖症和糖尿病。值得注意的是，我们强调G蛋白偶联受体 （GPCR）可能会导致新的药物治疗的发展，因为这些是目前最 用于药物靶向开发的大量研究的受体组。具体而言，GPR 149是孤儿GPCR 关于其在身体分布和生理作用方面知之甚少。然而，我们的实验室 最近发现，Gpr 149在参与能量调节的大脑回路中高度表达 体内平衡和进食。因此，我们的数据支持神经元GPR 149与未知的 控制能量稳态的神经通路的代谢线索。值得注意的是，使用CRISPR-Cas9 技术，我们已经产生了一种新的小鼠模型，允许删除内源性Gpr 149表达 以组织特异性的方式。使用这种小鼠模型，我们的建议将直接评估 GPR 149在能量平衡中的作用。最终，根据本RFA生成的数据将通过以下方式查找： 灯塔，并作为未来的努力，旨在了解GPR 149信号的基本作用的基础。

PROJECT SUMMARY/ABSTRACT The incidence of obesity and related disorders including diabetes mellitus continue to rise. Chronic over nutrition is prevalent, which has profound metabolic effects including causing increased systemic inflammation and altered hepatic glucose and lipid production. Research into the molecular mechanisms underlying energy balance are important for developing new prevention strategies, diagnostic tests and treatments in chronic metabolic diseases such as obesity and diabetes. Notably, our emphasis on a G-protein coupled receptor (GPCR) may lead to the development of novel pharmaceutical therapies, as these are currently the most heavily investigated receptor groups for drug target development. Specifically, GPR149 is an orphan GPCR about which very little is known in terms of body distribution and physiological role(s). However, our laboratory has recently found that Gpr149 is highly expressed in a brain circuit involved in the regulation of energy homeostasis and feeding. Hence, our data support the hypothesis that neuronal GPR149 links an unknown metabolic cue to the neural pathways controlling energy homeostasis. Notably, using the CRISPR-Cas9 technology, we have generated a novel mouse model allowing the deletion of endogenous Gpr149 expression in a tissue-specific manner. Using this mouse model, our proposal will directly assess the physiological role of neuronal GPR149 in energy balance. Ultimately, the data generated under this RFA will be findable through Pharos and serve as a basis for future efforts aimed at understanding the basic role of GPR149 signaling.