The goal of this research is to understand how cilia form and function. The nematode Caenorhabditis elegans is a powerful model system to study cilia biology. Many proteins that are required for formation, maintenance, and function of cilia in C. elegans are linked to human renal diseases, including autosomal dominant polycystic kidney disease (ADPKD). ADPKD affects 1 in 1000 individuals, often resulting in end-stage renal disease. In humans, mutations in the polycystin-1 (PC-1) or polycystin-2 (PC-2) ciliary mechanosensory complex cause ADPKD. In C. elegans, the polycystins LOV-1 and PKD-2 localize on the ciliary membrane and are required for sensory transduction. Hence, the connection between the polycystins and cilia seems to be an ancient one. The polycystins must ultimately be localized to cilia in order to conduct the sensory function of the cell, whether it is a human renal epithelial cell or a worm sensory neuron. How the polycystins and other ciliary proteins localize and gain access to the cilium, a spatially restricted organelle, is not known. In C. elegans it is possible to identify the mechanisms controlling polycystin ciliary localization and function in living animals. This study will use classical and reverse genetics, molecular biology, transgenic nematodes, microscopy, electrophysiology, calcium imaging, and biochemical methods to understand the regulation, function, and localization of the polycystins.
One specific aim i s to identify and characterize the molecular mechanisms regulating PKD-2/PC-2 ciliary protein localization and function.
A second aim i s to examine the role of the kinesin KLP-6 in ciliary protein transport and sensation, as well as identify KLP-6 cargoes.
A third aim i s to identify new genes required for ciliogenesis and polycystin ciliary localization. These studies in a tractable model organism will provide basic insights into the mechanisms governing cilia formation and function. ? ? ?
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