While considerable progress has been made in the characterization of the genes that cause PKD, the mechanism of the pathobiology in this disorder is still unknown. In particular, the potential utility of gene-based therapy for this disorder is not at all clear. In this regard, it is useful to consider alternative approaches to inhibit the progression of cystic degeneration in PKD. It is well known that the same underlying genetic defect in the PKD gene can have different degrees of severity, presumably as a function of the genetic background of the affected individual. This has led to the recognition of potential importance of modifier loci, which can influence the expression of the PKD defect. The localization of such modifying loci has been most successful in animal models of recessive PKD. While these are clearly different than human ADPKD, there exists the possibility that these modifying loci may have their effect on cystic disease progression irrespective of the underlying molecular defect. This possibility, combined with the powerful genomic tools that have been developed for positional cloning of genes in model organisms, provides strong support for a proposal to localize and clone modifiers of PKD progression in model organisms. We have extensive experience both in the analysis of modifying loci of PKD in mice, as well as the utilization of genomic technology for gene discovery, and we propose to apply this expertise to the characterization of a locus that appears to influence disease progression in several mouse mutant systems. Specifically, we plan to use congenic strains to identify a recombinant interval carrying the modifying loci. We will also use haplotype analysis, DNA sequencing and bioinformatic analysis to identify genes across the region, which can be considered as candidates for the modifying locus. In addition, we suggest that for the comprehensive analysis of genetic factors modulating PKD it is necessary to have a better model of the dominantly inherited PKD-predisposition characteristic of the human disease. It is therefore an aim of this proposal to develop mutant mice that develop cysts as a consequence of loss of heterozygosity, using either a spontaneous or inducible system.
| Beier, David R (2016) High-resolution genetic localization of a modifying locus affecting disease severity in the juvenile cystic kidneys (jck) mouse model of polycystic kidney disease. Mamm Genome 27:191-9 |
| Manning, Danielle K; Sergeev, Mikhail; van Heesbeen, Roy G et al. (2013) Loss of the ciliary kinase Nek8 causes left-right asymmetry defects. J Am Soc Nephrol 24:100-12 |
| Hellman, Nathan E; Liu, Yan; Merkel, Erin et al. (2010) The zebrafish foxj1a transcription factor regulates cilia function in response to injury and epithelial stretch. Proc Natl Acad Sci U S A 107:18499-504 |
| Smith, Laurie A; Bukanov, Nikolay O; Husson, Herve et al. (2006) Development of polycystic kidney disease in juvenile cystic kidney mice: insights into pathogenesis, ciliary abnormalities, and common features with human disease. J Am Soc Nephrol 17:2821-31 |
