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 i s 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). ? ? ?
|Tiwari, Sarika; Hudson, Scott; Gattone 2nd, Vincent H et al. (2013) Meckelin 3 is necessary for photoreceptor outer segment development in rat Meckel syndrome. PLoS One 8:e59306|
|Mason, Stephen B; Lai, Xianyin; Ringham, Heather N et al. (2011) Differential expression of renal proteins in a rodent model of Meckel syndrome. Nephron Exp Nephrol 117:e31-8|
|Ward, Heather H; Brown-Glaberman, Ursa; Wang, Jing et al. (2011) A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1. Mol Biol Cell 22:3289-305|
|Pluznick, Jennifer L; Rodriguez-Gil, Diego J; Hull, Michael et al. (2011) Renal cystic disease proteins play critical roles in the organization of the olfactory epithelium. PLoS One 6:e19694|
|Mason, Stephen B; Liang, Yun; Sinders, Rachel M et al. (2010) Disease stage characterization of hepatorenal fibrocystic pathology in the PCK rat model of ARPKD. Anat Rec (Hoboken) 293:1279-88|
|Tammachote, Rachaneekorn; Hommerding, Cynthia J; Sinders, Rachel M et al. (2009) Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3. Hum Mol Genet 18:3311-23|
|Mason, Stephen B; Lai, Xianyin; Bacallao, Robert L et al. (2009) The biomarker enriched proteome of autosomal dominant polycystic kidney disease cyst fluid. Proteomics Clin Appl 3:1247-1250|
|Muchatuta, Monalisa N; Gattone 2nd, Vincent H; Witzmann, Frank A et al. (2009) Structural and functional analyses of liver cysts from the BALB/c-cpk mouse model of polycystic kidney disease. Exp Biol Med (Maywood) 234:17-27|