Autosomal dominant polycystic kidney disease (ADPKD) is the most common lethal monogenic genetic diseases (ADPKD) of man, affecting ~1 in 1,000 individuals. ADPKD is characterized by focal dilatations of renal tubules that lead to cystic replacement of renal tissue and eventually renal failure, requiring renal replacement therapy in half of the cases by age 50. ADPKD is a systemic disease involving the kidney, liver, pancreas, arteries, and heart. Mutations in the PKD1 and PKD2 genes which encode polycystin-1 and -2 (PC1 and PC2), respectively, cause ADPKD. Mutations in the PKD1 gene alone are responsible for -85% cases of ADPKD. To study PKD7-disease, the principal investigator's group previously generated mice with two germline mutations (de!34 and null) targeted to the Pkd1 locus by homologous recombination in embryonic stem (ES) cells. Unfortunately, these mice, as well as all other Pkd1 mutants generated later, die between the 13th day of embryonic life and shortly after birth, which greatly limits the use of these animal models to answer a number of questions and prevented one from studying the role of PC1 in adult life. In the last funding period, the principal investigator developed a new line of germline Pkd1 mutant mice by creating an in-frame deletion (deletion of exon 2-6) in the extracellular domain of PC1 and a line of transgenic mice with exon 2-6 of Pkd1 flanked by loxP sites by homologous recombination in ES cells. The new germline Pkd1 mutant line differs from all existing Pkd1 mutant lines in not having an artificial insertion of a neomycin resistant cassette. Such an insertion has previously been reported to affect the expression of neighboring genes. In this proposal, the principal investigator aims to perform comparative studies of the phenotypes of the new germline mutant (cte/2-6) with existing Pkd1 mutants to determine the authentic phenotypes caused by Pkd1 mutations. She will use the newly developed Pkd1 floxed mice to generate tissue- and cell type-specific Pkd1 knockouts to provide a better animal model of the human disease, to study the role of PC1 in postnatal development and in adult life, and to test therapies that might palliate or cure PKDt-disease. She will test the "two-hit" hypothesis as a mechanism for cyst formation in ADPKD. The principal investigator's group has recently shown that PC1 and PC2 function as a mechanosensitive receptor-channel complex mediating Ca2+ signaling in cultured renal epithelia. In this proposal, she will test this hypothesis in vivo. These studies are likely to advance our knowledge on the molecular mechanisms of the disease and on the design of therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK051050-19
Application #
8668924
Study Section
Special Emphasis Panel (ZRG1-RUS-E (02))
Program Officer
Rasooly, Rebekah S
Project Start
1995-09-30
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
19
Fiscal Year
2014
Total Cost
$493,592
Indirect Cost
$213,403
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Wu, Yong; Xu, Jen X; El-Jouni, Wassim et al. (2016) Gα12 is required for renal cystogenesis induced by Pkd1 inactivation. J Cell Sci 129:3675-3684
Yao, Gang; Luo, Chong; Harvey, Michael et al. (2016) Disruption of polycystin-L causes hippocampal and thalamocortical hyperexcitability. Hum Mol Genet 25:448-58
Su, Xuefeng; Wu, Maoqing; Yao, Gang et al. (2015) Regulation of polycystin-1 ciliary trafficking by motifs at its C-terminus and polycystin-2 but not by cleavage at the GPS site. J Cell Sci 128:4063-73
DesRochers, Teresa M; Kimmerling, Erica Palma; Jandhyala, Dakshina M et al. (2015) Effects of Shiga toxin type 2 on a bioengineered three-dimensional model of human renal tissue. Infect Immun 83:28-38
Freedman, Benjamin S; Brooks, Craig R; Lam, Albert Q et al. (2015) Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat Commun 6:8715
Jin, Xingjian; Muntean, Brian S; Aal-Aaboda, Munaf S et al. (2014) L-type calcium channel modulates cystic kidney phenotype. Biochim Biophys Acta 1842:1518-26
Yao, Gang; Su, Xuefeng; Nguyen, Vy et al. (2014) Polycystin-1 regulates actin cytoskeleton organization and directional cell migration through a novel PC1-Pacsin 2-N-Wasp complex. Hum Mol Genet 23:2769-79
Aboualaiwi, Wissam A; Muntean, Brian S; Ratnam, Shobha et al. (2014) Survivin-induced abnormal ploidy contributes to cystic kidney and aneurysm formation. Circulation 129:660-72
Zeng, Liling; Bai, Ming; Mittal, Amit K et al. (2013) Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell carcinoma. Cancer Res 73:5371-80
Freedman, Benjamin S; Lam, Albert Q; Sundsbak, Jamie L et al. (2013) Reduced ciliary polycystin-2 in induced pluripotent stem cells from polycystic kidney disease patients with PKD1 mutations. J Am Soc Nephrol 24:1571-86

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