Towards a structural understanding of childhood obesity in Bardet-Biedl syndrome

描述（由申请人提供）：信号转导是细胞从环境中接收信号并将其传递的关键过程。近年来发现，许多信号转导途径都是利用初级纤毛作为“信号天线”。“受体和下游效应物的适当纤毛定位是激活基本信号通路如刺猬通路所必需的。因此，了解跨膜信号分子如受体如何正确靶向睫状膜而不是相邻的质膜或其他细胞区室是至关重要的。虽然通过分泌系统的其他部分进行的运输已经得到了很好的研究，但对蛋白质如何被分选到纤毛并运送到那里却知之甚少。许多多系统疾病，如Bardet-Biedl综合征（BBS），被认为是由纤毛信号改变引起的，这意味着大多数器官系统都需要初级纤毛。这项建议将集中在BBS的一个方面，肥胖。一些证据表明，BBS患者的肥胖是由信号受体如瘦素受体在功能性BBSome（BBS蛋白复合物）不存在的情况下的错误定位引起的。本研究将使用海马和下丘脑神经元中的生理相关细胞生物学研究来检查瘦素受体与BBSome的相互作用。负责其纤毛靶向的瘦素受体区域将被映射。还将检查BBSome在增强瘦素受体下游信号传导中的作用。此外，结构生物学，包括冷冻电子显微镜和X射线晶体学，将用于确定BBSome将信号受体转运到纤毛或纤毛内的分子机制。通过了解BBS中肥胖是如何发生的，我们可能会发现新的治疗靶点，从而为肥胖提供新的治疗方法。事实上，BBSome本身就是一个有吸引力的治疗靶点，因此确定其结构将提供设计药理学干预所需的分子细节。儿童肥胖是一个重要的公共卫生问题，我们将通过研究肥胖的遗传形式，Bardet-Biedl综合征（BBS）来解决。在这个项目中，我们将研究BBS蛋白质的稳定颗粒如何将体重传感器传输到细胞天线。了解体重是如何调节的可能会导致肥胖的新疗法。

DESCRIPTION (provided by applicant): Signal transduction is a key process through which a cell receives signals from the environment and relays them. It has recently been discovered that many signal transduction pathways utilize the primary cilium as a "signaling antenna." Proper ciliary localization of receptors and downstream effectors is required for activation of fundamental signaling pathways such as the Hedgehog pathway. Therefore, it is essential to understand how transmembrane signaling molecules such as receptors are correctly targeted to the ciliary membrane rather than the adjoining plasma membrane or other cellular compartments. While trafficking through other parts of the secretory system has been well studied, little is known about how proteins are sorted to the cilium and delivered there. A number of multi-system diseases, such as Bardet-Biedl syndrome (BBS), are thought to result from altered ciliary signaling, implying that primary cilia are required in most organ systems. This proposal will focus on one facet of BBS, obesity. Several lines of evidence suggest that obesity in BBS patients is caused by mislocalization of signaling receptors, such as the leptin receptor, in the absence of a functional BBSome (complex of BBS proteins). This study will examine the interaction of the leptin receptor with the BBSome using physiologically relevant cell biological studies in hippocampal and hypothalamic neurons. The region of the leptin receptor responsible for its ciliary targeting will be mapped. The role of the BBSome in potentiating signaling downstream of the leptin receptor will also be examined. In addition, structural biology, including cryo-electron microscopy and X-ray crystallography, will be used to determine the molecular mechanism by which the BBSome transports signaling receptors to or within the cilium. By learning how obesity occurs in BBS, we may discover new therapeutic targets that will allow for new treatments for obesity. Indeed, the BBSome itself is an attractive therapeutic target, so ascertaining its structure will provide the molecular detail that is required for designing pharmacologic interventions. Childhood obesity is a critical public health issue that we will address by studying an inherited form of obesity, Bardet-Biedl syndrome (BBS). In this project, we will examine how a stable particle of BBS proteins transports body weight sensors to the cellular antenna. Understanding how body weight is regulated may lead to new therapies for obesity.