Mechanisms of Ciliary Signaling Controlling Obesity and Metabolic Disease

这个项目的重点是了解一系列重要的 人类的生理信号，包括控制进食和肥胖。这一机制使用了一种古老的 细胞信号细胞器，初级纤毛，控制对摄食后产生的饱足信号的反应。 Bardet-Biedl综合征(BBS)是一种罕见的人类综合征，由于编码基因的突变而被称为睫状病 初级纤毛的组成部分。患有BBS的患者遗传了与一种名为 我们实验室发现的BBSome不能提供对限制餐后进食至关重要的受体。我们的 研究发现，纤毛还通过新脂肪细胞的从头生成和分泌 胰岛细胞中的胰岛素和胰升糖素。我们的重点是纤毛信号和贩运的机制， 通过使用亲和纯化/质谱学来识别睫状结构的新组件。 这些研究是通过使用睫状病疾病基因作为诱饵蛋白来寻找新的成分而开始的 以及与纤毛交通和信号相关的细胞生物通路。许多这些新发现的组件 在与肥胖有关的人类谱系中，它们自身也发生了突变。特别是，一种称为远端的纤毛结构 附属器是纤毛感受器进入的关键通道。我们发现远端组分的突变 附属物与单基因肥胖综合征有关。由于单基因肥胖综合征很少见，该实验室 在全基因组关联研究中，转向对超过75万名患者的公共数据进行系统调查 发现高体重指数(BMI)患者的基因改变(肥胖的关键指标)和 糖尿病。我们已经发现了100人，如果不是1000人的话，他们的候选人名单要大得多 肥胖驱动因素与非血缘关系人群中的纤毛有关。在本提案的目标1中，我们将进一步探讨 远端附属物组装的机制以及如何组织运输进入纤毛。在……里面 目的2，我们将研究远端附属器如何在细胞内传递受体并产生信号。在目标3中，我们 将探索远端附件的一种新因子，称为CCDC92，它可能通过蛋白分解来控制信号 破坏纤毛信号调节器。在每个目标中，我们将使用来自高血压病患者的基因损伤 我们发现的BMI已经筛选出纤毛运输或信号方面的缺陷。我们的目标是继续解释 肥胖损害，允许准确评估患者的遗传肥胖驱动因素，以识别额外的可用药 肥胖和糖尿病治疗的目标，并将这些发现传达给公众，以帮助预测饮食 基于分子遗传特征的易感性。通过识别肥胖和肥胖的信号通路缺陷 糖尿病，我们可以确定保护或恢复这些组织的靶组织和患者的分子图谱，以方便 选择患者进行改善肥胖和代谢性疾病的治疗。

This project focuses on understanding a fundamental cellular mechanism underlying a range of important physiological signaling in humans including the control of feeding and obesity. The mechanism uses an ancient cellular signaling organelle, the primary cilium, to control responses to satiety signals generated following feeding. Bardet-Biedl syndrome (BBS) is a rare human syndrome called a ciliopathy because of mutations in genes encoding components of the primary cilium. Patients with BBS have inherited mutations in genes linked to a complex called the BBSome, discovered in our laboratory, that fail to present receptors critical to limit feeding after a meal. Our work has found that cilia also control adipogenesis via the de novo generation of new fat cells and the secretion of insulin and glucagon in pancreatic islet cells. We have focused on mechanisms of ciliary signaling and trafficking, enabled by the use of affinity purification/mass spectrometry to identify new components of the ciliary machinery. These studies have been initiated by using the ciliopathy disease genes as bait proteins to find new components and cell biological pathways linked to ciliary traffic and signaling. A number of these newly discovered components are themselves mutated in human pedigrees linked to obesity. In particular, a ciliary structure called the distal appendage serves as a critical gate for entry of ciliary receptors. We find that mutations in components of the distal appendage are linked to monogenic obesity syndromes. As monogenic obesity syndromes are rare, the lab has shifted to systematically surveying public data for over 750,000 patients in Genome Wide Association Studies (GWAS) for genes found to be altered in patients with high Body Mass Index (BMI) (a key measure of obesity) and diabetes. We have discovered 100s if not 1000s of candidates for a substantially broader list of candidates for obesity drivers linked to cilia in nonconsanguineous populations. In Aim 1 of this proposal, we will further explore the mechanisms by which the distal appendage is assembled and how that organizes trafficking into the cilium. In Aim 2, we will examine how the distal appendage traffics receptors and generates signals in the cell. In Aim 3, we will explore a new factor of the distal appendage, called CCDC92, which potentially controls signaling via proteolytic destruction of ciliary signaling regulators. In each Aim, we will use genetic lesions derived from patients with high BMI which we find have screened for defects in ciliary trafficking or signaling. Our goals are to continue to explain obesity lesions to allow accurate assessment of a patient’s genetic obesity drivers, to identify additional druggable targets for obesity and diabetes therapeutics, and to communicate these findings to the public to help predict dietary susceptibilities based on molecular genetic profiles. By identifying signaling pathways defective in obesity and diabetes, we can identify targets to protect or restore these tissues and molecular profiles of patients to facilitate patient selection for treatments to improve obesity and metabolic disease.