Pathogenesis of wpk-induced Renal and Cerebral Disease

遗传性肾囊肿，包括各种形式的多囊肾病（PKD）是普遍存在的 通常会影响多个器官。有许多人类基因，当突变时， 导致多种囊性表型，并伴有不同的肾外表现。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， 但也可作为其它啮齿动物模型和人PKD的修饰基因。但这一切 模型为我们对PKD的认识做出了重要贡献。目前的建议将隔离大鼠 wpk基因导致类似于人类常染色体隐性PKD的肾脏变化。此外，受影响 大鼠具有类似于以下的脑缺陷（脑积水伴胼胝体发育不全或发育不全）： 在人类口面指、生殖髌和肾肾指综合征中可见。目前我们 将wpk基因定位于大鼠染色体5的2 Mb区域，该区域已知是啮齿动物PKD的藏身之处 修饰基因座和大约20个基因。我们研究的长期目标是确定基因和途径 参与肾囊肿形成，以便开发治疗干预措施。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）识别，克隆和 通过将Wistar-wpk大鼠与近交系Brown Norway大鼠杂交并使用 染色体标记来定位基因。除了位置方法，我们将确定候选人 用RT-PCR以及从该区域筛选大鼠ESTs来检测具有2 Mb区域的基因。 一旦确定，将使用9个器官表达和免疫组织化学来鉴定组织和细胞 表达这种基因产物。Wpk基因及其蛋白产物的鉴定将使人们了解 以及肾脏和大脑发育中共享途径的重要信息。 这种模型和Wpk基因是重要的2个主要原因，a）他们有囊性疾病和独特的 脑病理学类似于一些人类状况，和B）Wpk位于已知 修饰其它啮齿类形式的PKD，并且可能是PKD（啮齿类和人）的重要修饰基因座。

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 Chromosme 5, a location known to harbour 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).