Molecular mechanism of renal deciliation and cystogenesis

University Of Iowa, Iowa City IA

Investigators

Abstract

DESCRIPTION (provided by applicant): Polycystic kidney diseases (PKD) affect more than 600,000 Americans and 12.5 million people worldwide. Scientists have made significant progress toward understanding the cellular basis of PKD following the discovery that primary cilia, special sensory organelles present on nearly all cells, are either absent or function abnormally in PKD. However, molecular mechanisms linking aberrant ciliary function with renal cystogenesis are incompletely understood. The long-term goal of our research is to understand how primary cilia transmit environmental signals to intercellular junctions and the secretory apparatus to regulate surface polarity and transport activities of renal epithelial cells in order to comprehend and develop new treatments for PKD. This proposal is focused on molecular mechanisms of renal epithelial deciliation (autotomy) and consequences of ciliary loss on cell polarity, transport functions and proliferation. Based upon results of preliminary studies, a working hypothesis has been developed. We hypothesize that quiescent cells activate an evolutionarily conserved signaling pathway resulting in ciliary excision as part of a normal sequence of events before re-entering the cell cycle. Our working model is that mutations in proteins that function in this pathway contribute to renal cystogenesis by promoting uncontrolled cell growth and altering trans-epithelial transport functions. In this proposal, we aim to dissect the molecular mechanism of renal deciliation and to determine how ciliary shedding alters the organization of kidney epithelial cells, such that cysts are formed. The specific aims of this study are: 1) to determine whether renal ciliary shedding occurs in vivo and whether it is associated with PKD;2) to identify and understand molecular mechanisms of renal ciliary autotomy, focusing primarily on the NIMA-related kinase Nek8, an ortholog of a component required for flagellar excision in green algae and the mutated protein in the juvenile cystic kidney (jck) murine model of autosomal recessive PKD;and 3) to determine how deciliation alters transport properties and growth regulation of kidney epithelial cells leading to cyst formation. The significance of these studies is that they will deepen our understanding of a neglected aspect of the cell biology of renal cystogenesis and potentially lead to discovery of new therapies for PKD.