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 ta...