Sensing and responding to the environment is critical for all living beings. Most sensory system utilizes cilia to sense stimuli and convert into physiological response. Cilia are microtubule-based sensory organelles that extending from the cell surfaces of most eukaryotic organisms. Although identified nearly 100 years ago, the cilia were overlooked for a long time. Recently, researches from C. elegans and other model organisms implied a surprising connection between the defects in normal cilium sensory function and a wide spectrum of mammalian pathologies. Strikingly, in nematode C. elegans, many genes encoding ciliary components involved in cilia biogenesis and cilia function have mammalian counterparts that when mutated cause cilia diseases with renal cyst pathologies, such as Autosomal Dominant Polycystic Kidney Disease (ADPKD), Autosomal Recessive PKD (ARPKD), Nephronophthisis (NPHP), Bardet-Biedl syndrome (BBS) and Meckel-Gruber Syndrome (MKS). The evolutionarily conserved cilia pathological genes, ciliary localization, and sensory function make the nematode an attractive model to study cilia biogenesis, cilia function, and cilia-related human renal diseases.

The long-term goal of our lab is to understand how cilia form and function, and to relate these findings to human cilia diseases. Given that it is prohibitively difficult in humans to study these questions, alternative experimental systems are necessary. In C. elegans we can explore all these questions in living animal. Results of our proposed studies will provide new insight and possible novel intervention point into the molecular basis of cystic kidney diseases and broaden our understanding of how cilia develop and function in normal and pathological states.

Current research projects 1. Cilia biogenesis. Our knowledge about how cilia biogenesis happens in vivo is obscure. To explore the fundamental question about how cilia biogenesis happens in vivo, three experimental approaches are designed. Genome-wide genetic screening has been used to screening C. elegans mutants with ciliogenesis defects. Over 200 mutants have been isolated, and mapping is in progress. At same time, functional genomics and functional proteomics will be used to Identify core machinery of ciliogenesis. 2. Polycystin function. ADPKD (autosomal dominant polycystic kidney disease ), the most common genetic disease in human, affects 1 in 1000 individuals and is caused by defects in polycystin-1 (PC-1, encoded by PKD1) or polycystin-2 (PC-2, encoded by PKD2). Many basic questions in polycystin biology remain unresolved. Using C. elegans as a model, we are studying the cleavage of polycystin-1 and its significance, the channel activity of polycystin complex, other critical signaling components involved in polycystin functional pathway, and other sensory complex that functions with or in parallel to polycystins on cilia.

3. Polycystin ciliary localization. Remarkably little is known about how polycystins, signaling molecules, and structural components are targeted to the ciliary compartment and how this ciliary localization is maintained. Our previous data suggest that cilia base/(transition zone) is a critical site for ciliary proteins to be unloaded/loaded and recycled/degraded. More experimental approaches will be used to determine if the cilia base function as hot spot for shipping, receiving and downregulation of polycystins and their signaling molecules.