Pathogenesis of wpk-induced Renal and Cerebral Disease

描述（由申请人提供）：遗传性肾脏囊性疾病，包括各种形式的多囊肾病（PKD），是通常影响多个器官的常见疾病。有许多人类基因，当突变时，导致各种囊性表型与可变的肾外表现。有几种啮齿动物模型，其中一些在已知的人类PKD基因中具有突变。其他模型代表啮齿动物PKD基因，但也可以作为其他啮齿动物模型和人类PKD的修饰基因。然而，所有这些模型都为我们对PKD的认识做出了重要贡献。目前的建议将分离大鼠wpk基因，导致肾脏的变化类似于人类常染色体隐性PKD。此外，受影响的大鼠具有脑缺陷（脑积水伴胼胝体发育不全或发育不全），类似于在人类口面指、生殖髌和肾-指综合征中观察到的缺陷。目前，我们将wpk基因定位于大鼠5号染色体的2 Mb区域，该位置已知含有啮齿动物PKD修饰基因座和约20个基因。我们研究的长期目标是确定参与肾囊肿形成的基因和途径，以开发治疗干预措施。我们假设Wpk基因代表人PKD基因和/或修饰基因座。我们的具体目标是：1）通过将Wistar-wpk大鼠与近交系Brown Norway大鼠杂交并使用染色体标记定位Wpk基因来鉴定、克隆和表征Wpk基因。除了定位的方法，我们将确定候选基因与2 Mb区域进行测试，使用RT-PCR以及筛选大鼠EST从该地区。一旦鉴定，将使用9器官表达和免疫组织化学来鉴定表达该基因产物的组织和细胞。Wpk基因及其蛋白产物的鉴定将使我们能够深入了解囊肿形成以及肾脏和大脑发育中共享途径的重要信息。该模型和Wpk基因是重要的，主要有两个原因，a）它们具有类似于少数人类病症的囊性疾病和独特的大脑病理学，和B）Wpk位于已知修饰其他啮齿类形式的PKD的染色体区域，并且可能是PKD（啮齿类和人类）的重要修饰基因座。

DESCRIPTION (provided by applicant): Inherited renal cystic diseases, including the various forms of polycystic kidney disease (PKD) are prevalent conditions that usually affects multiple organs. There are numerous human genes, which when mutated, lead to a variety of cystic phenotypes with variable extrarenal manifestations. There are several rodent models, some with mutations in known human PKD genes. Others models represent rodent PKD genes, but could also function as modifier genes for other rodent models and human PKD. However, all of these models have made important contributions to our knowledge of PKD. The present proposal will isolate the rat wpk gene which causes renal changes similar to human autosomal recessive PKD. Additionally, affected rats have a cerebral defect (hydrocephalus with agenesis or hypoplasia of the corpus callosum) similar to that seen in human oro-facial-digital, genitopatellar and cerebro-renal-digital syndromes. Currently we localized the wpk gene to a 2Mb region of rat Chromosome 5, a location known to harbor a rodent PKD modifier locus and about 20 genes. The long term goal of our research is to identify genes and pathways involved in renal cystogenesis in order to develop therapeutic interventions. We hypothesize that the Wpk gene represents a human PKD gene and/or a modifier locus. Our Specific Aim is to: 1) Identify, clone and characterize the Wpk gene by crossing the Wistar-wpk rat with inbred Brown Norway rats and using chromosomal markers to localize the gene. Aside from the positional approach, we will identify candidate genes from with the 2Mb regions to test using RT-PCR as well as by screening rat ESTs from that region. Once identified, 9organ expression and immunohistochemistry will be used to identify the tissues and cells that express this gene product. The identification of the Wpk gene and its protein product will allow insight into cystogenesis as well as important information on shared pathways in kidney and brain development. This model and the Wpk gene are important for 2 major reasons, a) they have cystic disease and unique cerebral pathology similar to a few human conditions and b) the Wpk lies in a chromosomal region known to modify other rodent forms of PKD and may be an important modifier locus for PKD (rodent and human).