Cell biology of autosomal dominant polycystic kidney disease

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DESCRIPTION (provided by applicant): The primary cilium, now known as a sensory organelle and a signaling center present in almost all cells, has attracted much attention in the past decade due to its role in a large group of diseases with cystic kidney phenotype. Gene depletion and deletion experiments, and human genetics have shown that either a structural or a functional defect in the primary cilium of kidney epithelial cells leads to cyst formation. The growing group of human diseases with ciliary defects and phenotypes including cystic kidneys, obesity, blindness and mental retardation, are now collectively regarded as ciliopathies. Autosomal dominant polycystic kidney disease (ADPKD), the most common form of ciliopathy, has been a long-standing research focus of my lab. Most studies on ADPKD have focused on how loss of PC1 protein leads to a number of cellular defects in ADPKD though a large number of ADPKD pedigrees have mutations that lead to defective targeting of the mutant proteins to their normal functional sites. At present little is known about the structural determinants for membrane proteins to traffic to the primary cilia and the cellular machinery required for this process. Mechanisms by which full-length PC1 traffics to the primary cilium are unknown. We propose that elucidating the mechanisms by which PC1 traffics to the primary cilia is central to understanding PC1 function and the pathogenesis of ADPKD, as well as to the design of therapeutics for ADPKD. We have designed two aims. Aim 1: Elucidate the structural determinants in PC1 responsible for its targeting to the primary cilia; Aim 2: Determine the machinery used for PC1 trafficking to the ciliary membrane.