Presented in this proposal is a structured research training program that provides the candidate with extensive training in molecular and cell biology along with a foundation for a doctoral dissertation and transition to an independent investigator. The basis of the research plan is the molecular analysis and pathophysiology of a newly identified insertional mutation in the mouse that causes a form of polycystic kidney disease with a liver and kidney pathology that closely resembles that in human patients with autosomal recessive polycystic kidney disease (ARPKD). The first phase of this program will involve a total of 3 specific aims that will be directed at further characterizing the cellular and molecular biology of renal cyst formation and identifying and characterizing other genes that are in the same cystogenic pathway as the Tg737 gene.
these specific aims are: 1) determine the effects of paclitaxel on cystic kidney and liver lesions in the TgN737Rpw mutant line, 2) investigate the effects of phenotypic rescue of the kidney trait in the TgN737pw mutant line, 3) determine the chromosomal location of the modifier genes that influence the varied phenotypic expression of TgN737Rpw between the FVB/N and C3Hf/R1 inbred genetic backgrounds. Phase II of the proposal at this time will be a continuation of Aim 3 to further identify the modifier genes influencing the TgN737Rpw phenotype. The identification of these modifier genes will be helpful in understanding the pathogenesis of PKD and provide possibilities for new areas of treatment to stop the progression of PKD. Furthermore, at least some of these genes may be in the same common pathway of cyst generation and their identification will be especially valuable. The research training and experience received through this training will provide the Candidate with a strong career development program in preparation for a research career.
| Sommardahl, C; Cottrell, M; Wilkinson, J E et al. (2001) Phenotypic variations of orpk mutation and chromosomal localization of modifiers influencing kidney phenotype. Physiol Genomics 7:127-34 |
