Cux-1 and cell cycle regulation in kidney development

描述(由申请人提供)：本提案的总体目标是 确定同源盒基因Cux-1在细胞周期调控中的作用 肾脏。Cux-1是果蝇基因Cut的小鼠同源物，它是 对马氏管的正常发育是必需的，这种昆虫 排泄和渗透调节器官。哺乳动物切割的同源物的功能是 终末分化相关基因的转录抑制因子 多种细胞谱系。CUX-1是控制G1-S网络的一部分 转换，其中它抑制细胞周期蛋白激酶抑制物的表达 (CKI)p21在S期。最近的研究表明，Cux-1的放松管制在 转基因小鼠导致p27kip1表达下调 肾发生、肾组织增生和系膜细胞增殖。系膜 细胞增殖与基质积累有关，并先于 肾小球硬化的进展。拟议的研究将测试 正常肾脏中Cux-1调控细胞增殖的假说 而Cux-1的解除调控有助于免疫调节和 非免疫性肾损伤。具体目标是：(I)履行 转基因大鼠肾脏发育的形态和生理评价 组成性表达Cux-1的小鼠；(Ii)进行原代系膜细胞的研究 从野生型和转基因肾脏中分离细胞以确定PDGF 碱性成纤维细胞生长因子诱导的CKI p27下调是由Cux-1介导的；(Iii) 评估Cux-1是否与p27启动子结合，并确定Cux-1是否 抑制p27基因表达；(Iv)确定Cux-1是否抑制p21和/或p27 在肾脏炎症损伤过程中，以及这是否会导致进一步的 肾功能减退。这些研究将为我们提供新的见解 肾脏疾病中细胞增殖的机制，并可能提供未来 肾脏疾病的治疗策略。

DESCRIPTION (provided by applicant): The overall aim of this proposal is to determine the role of the homeobox gene Cux-1 in cell cycle regulation in the kidney. Cux-1 is the murine homologue of the Drosophila gene Cut, which is required for the proper development of the Malpighian tubules, the insect excretory and osmoregulatory organs. Mammalian Cut homologues function as transcriptional repressors of genes specifying terminal differentiation in multiple cell lineages. Cux-1 is part of the network controlling G1-S transition, where it represses the expression of the cyclin kinase inhibitor (CKI) p21 in S phase. Recent studies demonstrate that deregulation of Cux-1 in transgenic mice results in down regulation of p27kip1 expression during nephrogenesis, renal hyperplasia, and mesangial cell proliferation. Mesangial cell proliferation is linked to matrix accumulation and precedes the development of glomeruloscierosis. The proposed studies will test the hypotheses that Cux-1 regulates cell proliferation during normal renal development, and that dereguletion of Cux-1 contributes to immune mediated and non-immune mediated renal injury. The specific aims are: (I) Perform morphological and physiological evaluations of developing kidneys in transgenic mice constitutively expressing Cux-1; (ii) perform studies on primary mesangial cells isolated from wild type and transgenic kidneys to determine whether PDGF and bFGF induced down regulation of the CKI p27 is mediated by Cux-1; (iii) evaluate whether Cux-1 binds to the p27 promoter, and determine whether Cux-1 represses p27 gene expression; (iv) determine if Cux-1 represses p21 and/or p27 during renal inflammatory injury, and whether this results in a further diminution of renal function. These studies will provide novel insights into the mechanisms of cell proliferation in renal disease, and may provide future therapeutic strategies for renal disease.