Role of Cilia in Renal Fibrosis

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Summary The cilium is a widely distributed cell surface organelle that functions as a signaling hub for the vertebrate cell. Ciliary defects leads to a wide range of human diseases collectively referred to as ciliopathies. Multiple ciliopathies, including nephronophthisis, show renal fibrosis. However, the role of cilia in renal fibrosis has not been studied extensively. In this project, we use Arl13b, a gene essential for cilia biogenesis, as an entry point to dissect the role of cilia in renal fibrosis. We generated conditional Arl13b knockout mice. Our results show that deletion of Arl13b in renal epithelial cells leads to renal fibrosis and cysts. Moreover, multiple signaling pathways, including the Wnt, HH and Hippo pathway, are mis-regulated in the mutant kidney. This project focuses on dissecting tissue specific functions of cilia and communications between different cell types in renal fibrosis through both candidate and unbiased approaches. Aim 1 is focused on signaling in renal epithelial cells regulated by ciliary defects and the relationship between different pathways. Aim 2 studies targets in interstitial cells that are affected by ciliary defects and the functional significance of interstitial cilia. Through this study, we will elucidate how ciliary defects in epithelial cells triggers a signaling cascade that eventually lead to renal fibrosis and whether and how cilia in interstitial cells modify this response. These results not only will provide insight to the mechanism of renal fibrosis in ciliopathies, but will also be informative to fibrosis in general.