The primary interest of our research program is unraveling the pathogenesis of human autosomal dominant polycystic kidney disease (ADPKD) with a final goal of developing rational therapeutic interventions to benefit affected patients. To this end, we used homologous recombination-based approaches to inactivate the Pkd 2 gene in mice and produce an adult animal model that recapitulate the human ADPKD phenotype. This animal model has proven the 'two hit' mechanism of cyst formation in PKD2. This work has convinced us that a complete understanding of polycystic kidney disease requires 1) the further development and steady of whole animal model systems and 2) the discovery of additional components in the 'polycystin' pathways. In keeping with this overall approach toward understanding and treating this human disease, our specific aims are: To determine the mechanisms by which polycystin-2 acts to maintain normal renal tubular architecture by producing an animal model in which we have temporal and spatial control of cyst formation. Specifically, we will make a mouse line bearing a floxed exon 3 of the Pkd2 gene and a pair orf inducible-Cre recombinase transgenic lines using the tamoxifen-inducible CreERTM transgene-one under the control of a collecting duct epithelial cell-specific promoter (Ksp- cadherin; cadherin) and another under a general promoter (pCAGGS; CMV-IE enhancer and a modified chicken beta-actin promoter). We will use these models to study the mechanisms of cyst formation in adult animals with ADPKD. In order to analyze structure function relationships and tissue-specific effects of Pkd2 using in vivo model system we will determine the effects of functional re-expression of a Pkd2 EF-hand mutant deficient in binding calcium and of a form of Pkd lacking the putative ER-localization domain. Finally, in order to identify downstream regulators whose expression is effected inactivation of Pkd we will generate well characterized cell lines from adult nephron segments that are genetically identical except for the presence or absence of functional polycystin-2 and profile the gene expression pattern in these cell lines to identify elements whose expression is altered by the loss of polycystin-2 function.
| Li, Ao; Tian, Xin; Zhang, Xiaoli et al. (2015) Human polycystin-2 transgene dose-dependently rescues ADPKD phenotypes in Pkd2 mutant mice. Am J Pathol 185:2843-60 |
| Merrick, David; Bertuccio, Claudia A; Chapin, Hannah C et al. (2014) Polycystin-1 cleavage and the regulation of transcriptional pathways. Pediatr Nephrol 29:505-11 |
| Cai, Yiqiang; Fedeles, Sorin V; Dong, Ke et al. (2014) Altered trafficking and stability of polycystins underlie polycystic kidney disease. J Clin Invest 124:5129-44 |
| Paavola, Jere; Schliffke, Simon; Rossetti, Sandro et al. (2013) Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. J Mol Cell Cardiol 58:199-208 |
| Yuan, Shiaulou; Zhao, Lu; Sun, Zhaoxia (2013) Dissecting the functional interplay between the TOR pathway and the cilium in zebrafish. Methods Enzymol 525:159-89 |
| Parikh, Chirag R; Dahl, Neera K; Chapman, Arlene B et al. (2012) Evaluation of urine biomarkers of kidney injury in polycystic kidney disease. Kidney Int 81:784-90 |
| Kuo, Ivana Y; Ehrlich, Barbara E (2012) Ion channels in renal disease. Chem Rev 112:6353-72 |
| Yoshiba, Satoko; Shiratori, Hidetaka; Kuo, Ivana Y et al. (2012) Cilia at the node of mouse embryos sense fluid flow for left-right determination via Pkd2. Science 338:226-31 |
| ?eli?, Andjelka S; Petri, Edward T; Benbow, Jennifer et al. (2012) Calcium-induced conformational changes in C-terminal tail of polycystin-2 are necessary for channel gating. J Biol Chem 287:17232-40 |
| Takiar, Vinita; Mistry, Kavita; Carmosino, Monica et al. (2012) VIP17/MAL expression modulates epithelial cyst formation and ciliogenesis. Am J Physiol Cell Physiol 303:C862-71 |
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