The gene products of the major forms of human polycystic kidney disease, polycystin-1, polycystin-2 and fibrocystin/polyductin all localize to th primary cilium. The primary cilium appears to be the major functional site for these proteins as mutations that affect ciliary structure also cause cystic disease. The mechanism by which membrane proteins like the polycystins and fibrocystin are trafficked to the cilium is largely unknown. Our long term goal is to understand how the cilium is assembled and how ciliary dysfunction leads to diseases like polycystic kidney disease. The hypothesis that drives our work is that the intraflagellar transport (IFT) system is critical for the assembly of both the cytoskeleton and the delivery of membrane proteins to the cilium. In particular, we focus our studies on the function of IFT20, which is localized to both the Golgi and ciliary compartments and is trafficked between the two organelles. IFT20 is absolutely required for ciliary assembly and its deletion from the kidney leads to severe polycystic kidney disease. This protein functions with a golgin protein GMAP210 in the delivery of polycystin-2 to cilia. It is likely that IFT20 functions in the context of membrane protein transport and a number of general trafficking proteins have been proposed to be involved in the movement of membrane proteins to cilia. In this proposal we seek to understand how the ciliary membrane proteins like the polycystins and fibrocystin are trafficked to the cilium. This will be carried by a combination of in vitro studiesof trafficking using a SNAP-tag based pulse-chase assay and in vivo studies of mutant mice.
Polycystic kidney is a major cause of end stage renal disease in the United States and throughout the world. The proteins encoded by the genes that are defective in polycystic kidney disease (the cystoproteins) localize to the primary cilium. This proposal seeks to understand the mechanism by which cystoproteins are trafficked to the primary cilium with the ultimate goal of modulating ciliary function to mitigate the disease.
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