Role of Cilia in Renal Fibrosis

纤毛在肾纤维化中的作用

• 批准号: 10153778
• 负责人: ZHAOXIA SUN
• 金额: $ 37.69万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153778
• 关键词: Affect; Back; Cell surface; Cells; Cilia; Communication; Complex; Cyst; Cystic kidney; Defect; Disease; Disease Progression; Distal; Epithelial; Epithelial Cells; Erinaceidae; Feeds; Fibroblasts; Fibrosis; Genes; Kidney; Knockout Mice; Lead; Ligands; Mental Retardation; Modeling; Monomeric GTP-Binding Proteins; Mus; Mutant Strains Mice; Myofibroblast; Nephronophthisis; Nephrons; Obesity; Organelles; Pathway interactions; Pattern; Phenotype; Polycystic Kidney Diseases; Retinal Degeneration; Role; Signal Pathway; Signal Transduction; Smooth Muscle Actin Staining Method; Testing; Tissues; base; cell type; ciliopathy; cilium biogenesis; human disease; insight; interstitial; interstitial cell; kidney fibrosis; mutant; paracrine; renal epithelium; response; smoothened signaling pathway

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.

概括 纤毛是一种广泛分布的细胞表面细胞器，充当脊椎动物细胞的信号中枢。 纤毛缺陷会导致多种人类疾病，统称为纤毛病。多种的 纤毛病，包括肾结核，表现出肾纤维化。然而，纤毛在肾纤维化中的作用尚未明确。 被广泛研究。在这个项目中，我们使用 Arl13b（纤毛生物发生必需的基因）作为切入点 剖析纤毛在肾纤维化中的作用。我们生成了条件性 Arl13b 基因敲除小鼠。我们的结果显示 肾上皮细胞中 Arl13b 的缺失会导致肾纤维化和囊肿。此外，多重信令 包括 Wnt、HH 和 Hippo 通路在内的通路在突变肾脏中受到错误调节。这个项目 专注于解剖纤毛的组织特异性功能以及肾中不同细胞类型之间的通讯 通过候选方法和公正的方法来抑制纤维化。目标 1 专注于肾上皮细胞中的信号传导 受纤毛缺陷和不同途径之间关系的调节。目标 2 研究插页式广告中的目标 受纤毛缺陷影响的细胞以及间质纤毛的功能意义。通过这项研究，我们 将阐明上皮细胞中的纤毛缺陷如何触发信号级联反应，最终导致肾损伤 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 深入了解纤毛病中肾纤维化的机制，但也将为一般纤维化提供信息。