Pathogenesis of wpk-induced Renal and Cerebral Disease

遗传性肾囊性疾病，包括各种形式的多囊肾病(Pkd)非常普遍。 通常会影响多个器官的情况。有许多人类基因，当它们发生突变时， 导致各种囊性表型，并伴有不同的肾外表现。有几只啮齿动物 模型，其中一些带有已知人类PKD基因的突变。其他模型代表了啮齿动物的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 模型为我们对PKD的认识做出了重要贡献。目前的提议将隔离老鼠 导致肾脏改变的WPK基因类似于人类常染色体隐性遗传性PKD。此外，受影响的 大鼠的脑缺陷(脑积水伴胼胝体发育不全或发育不良)类似于 这一点见于人类口腔-面部-指端、生殖椎和脑-肾-指端综合征。目前我们 将WPK基因定位于大鼠染色体5的2Mb区域，该区域已知含有啮齿动物PKD 修饰基因和大约20个基因。我们研究的长期目标是确定基因和途径 参与肾囊肿的发生，以开发治疗干预措施。我们假设朝鲜劳动党 基因代表人类PKD基因和/或修饰基因。我们的具体目标是：1)识别、克隆和 将Wistar-WPK大鼠与近交系棕色挪威大鼠杂交并使用 染色体标记来定位该基因。除了定位方法外，我们还将确定候选人 使用RT-PCR以及从该区域筛选大鼠EST来检测来自2Mb区域的基因。 一旦鉴定，将使用器官表达和免疫组织化学来鉴定组织和细胞 来表达这种基因产物。WPK基因及其蛋白产物的鉴定将使我们能够洞察 囊性发生以及有关肾脏和大脑发育的共同途径的重要信息。 这一模型和WPK基因之所以重要，主要有两个原因：a)它们有囊性疾病，并且 大脑病理类似于一些人类情况和b)WPK位于已知的染色体区域 修饰其他啮齿动物形式的PKD，可能是PKD(啮齿动物和人类)的重要修饰基因。

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).