MAPPING MOUSE LOCI THAT MODIFY CPK-INDUCED PKD

多囊肾病（PKD）的治疗方法有哪些？ 肾囊肿的治疗方法有哪些尽管最近在 克隆了几个人PKD基因，它们在疾病发病机制中的作用仍然存在， 未定义。此外，遗传背景似乎也会影响 许多PKD疾病易感基因的表达。表征 这些假定的修饰基因在复合体中将是相当困难的， 随机交配的人类作为替代，小鼠PKD突变 它们的基因修饰物可能为研究基因提供强大的资源 以及参与肾囊肿形成的基因相互作用。 在PKD分离为单个细胞的几种小鼠模型中， 孟德尔性状，三个突变，cpk，bpk和Tg737Rpw，非常类似于 人类常染色体隐性遗传性多囊肾病（ARPKD）。在这三 小鼠模型以及人ARPKD，肾囊肿形成始于子宫内 遗传背景影响疾病表达。所以我们 假设这些哺乳动物基因和它们的修饰物定义了 在肾囊肿的发生和发展过程中， 肾小管分化 在这个建议中，我们将识别和描述影响基因， cpk突变的表达。具体来说，我们将识别基因 会加速肾囊肿的发展， 在F2受影响的后代的亚种间的平板异常 C57BL/6J-cpk/+与小家鼠（Mus mus castaneus）杂交。另外我们 将绘制bpk突变，人类ARPKD的第二个小鼠模型。然后在一个 我们将测试cpk基因修饰剂是否影响 bpk突变的表型表达。最后，我们将构建 同源菌株，其在特定的细胞中分离单独的修饰基因座， 遗传背景作为识别和表征这些基因的前奏 基因.因此，本项目将建立分子框架， 鉴定修饰小鼠隐性遗传疾病发病机理的基因 PKD。我们的最终目标是利用这些遗传工具来解剖 人类ARPKD的分子发病机制。

A major focus in polycystic kidney disease (PKD) research is to identify genes involved in renal cyst development. Despite recent successes in cloning several human PKD genes, their roles in disease pathogenesis remain undefined. In addition, it appears that genetic background influences the expression of many PKD disease-susceptibility genes. The characterization of these putative modifying genes will be quite difficult in the complex, randomly mating, human population. As an alternative, mouse PKD mutations and their genetic modifiers may provide powerful resources to study genes and gene interactions involved in renal cystogenesis. Among the several mouse models in which PKD segregates as a single Mendelian trait, three mutations, cpk, bpk, and Tg737Rpw, closely resemble human autosomal recessive polycystic kidney disease (ARPKD). In these three mouse models as well as human ARPKD, renal cyst formation begins in utero and genetic background influences disease expression. Therefore, we hypothesize that these mammalian genes and their modifiers define a molecular pathway that is important in both renal cyst development and renal tubular differentiation. In this proposal, we will identify and characterize genes that influence the expression of the cpk mutation. Specifically, we will identify genes that accelerate the-development of renal cystic disease and cause bile duct plate abnormalities in the F2 affected progeny of an intersubspecific intercross between C57BL/6J-cpk/+ and Mus mus castaneus. In addition, we will map the bpk mutation, a second mouse model of human ARPKD. Then in a directed fashion, we will test whether the cpk genetic modifiers influence the phenotypic expression of the bpk mutation. Finally, we will construct congenic strains which isolate individual modifying loci in specific genetic backgrounds as the prelude to identifying and characterizing these genes. Therefore, this project will establish the molecular framework for identifying gene(s) that modify the disease pathogenesis in mouse recessive PKD. Our ultimate goal Is to use these genetic tools to dissect the molecular pathogenesis of human ARPKD.