Role of Cilia in Renal Fibrosis

总结 纤毛是一种广泛分布的细胞表面细胞器，作为脊椎动物细胞的信号中枢。 纤毛缺陷导致广泛的人类疾病，统称为纤毛病。多 包括肾单位萎缩在内的纤毛病表现为肾纤维化。然而，纤毛在肾纤维化中的作用还没有得到证实。 被广泛研究。在这个项目中，我们使用Arl13b，纤毛生物发生所必需的基因，作为切入点， 剖析纤毛在肾纤维化中的作用。我们产生了条件性Arll3b敲除小鼠。我们的研究结果表明 肾上皮细胞中Arl13b的缺失导致肾纤维化和囊肿。此外，多个信令 包括Wnt、HH和Hippo通路在内的多个信号通路在突变肾中被错误调节。这个项目 重点是解剖纤毛的组织特异性功能和肾脏中不同细胞类型之间的通讯。 通过候选和无偏见的方法。目的1是集中在肾上皮细胞的信号 调节纤毛缺陷和不同途径之间的关系。目的2研究间质中的靶点 纤毛缺陷影响的细胞和间质纤毛的功能意义。通过这项研究，我们 将阐明上皮细胞的纤毛缺陷如何触发信号级联反应，最终导致肾脏疾病。 纤维化以及间质细胞中的纤毛是否以及如何改变这种反应。这些结果不仅将提供 深入了解纤毛疾病中肾纤维化的机制，但也将为一般纤维化提供信息。

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.