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dc.contributor.advisorVanden Heuvel, Gregory Ben_US
dc.contributor.authorPaul, Binu M.
dc.date.accessioned2011-11-13T01:39:25Z
dc.date.available2011-11-13T01:39:25Z
dc.date.issued2011-08-31en_US
dc.date.submitted2011en_US
dc.identifier.otherhttp://dissertations.umi.com/ku:11721en_US
dc.identifier.urihttp://hdl.handle.net/1808/8384en_US
dc.description.abstractAutosomal dominant polycystic kidney disease (ADPKD) is a life-threatening genetic disorder characterized by the presence of fluid-filled cysts primarily in the kidneys. Mutations in either the PKD1 or PKD2 genes are the underlying cause of ADPKD. It is a systemic disorder and some of the extra-renal manifestations include polycystic liver, cerebral aneurysms, cardiac valve abnormalities and hypertension. Progressive cyst formation and renal enlargement lead to renal insufficiency in these patients which need to be managed by life-long dialysis or renal transplantation. Epithelial cell proliferation and fluid secretion are two hallmark features of PKD. Cux1 is a homeobox gene involved in cell cycle regulation during kidney development. In the developing mouse kidney, Cux1 is highly expressed in the nephrogenic zone where developing nephrons are present. Cux1 regulates the cell cycle by transcriptional repression of the cyclin dependent kinase inhibitors, p21 and p27, thereby increasing cell proliferation. As kidney development ceases, Cux1 is downregulated and adult kidneys show only low levels of Cux1. Cux1 is ectopically expressed in several mouse models of PKD, as well as, in ADPKD patients. Cux1 transgenic mice which overexpress Cux1 develops multiorgan hyperplasia including kidney hyperplasia, but they do not develop PKD. This suggests that the overexpression of Cux1 and the resultant increase in cell proliferation is not sufficient to cause PKD. In this particular study, we addressed the hypothesis that Cux1 is required for cystogenesis and/or cyst progression in ADPKD. Results from our mouse model which carries a collecting duct specific deletion in the Pkd1 gene (Pkd1CD) and a homozygous deletion in the Cux1 gene shows that the complete loss of Cux1 results in slowing the cyst initiation process. Moreover, a reduction in the gene dosage of Cux1 in Pkd1CD mice led to a slow progression of PKD resulting in the amelioration of the disease. The complete loss of the Cux1 gene and a reduction in its gene dosage mediated its effects by the de-repression of the p27 gene resulting in reduced cell proliferation. These studies point towards the importance of cell proliferation in the pathogenesis of PKD and show that Cux1 is required for cyst progression in ADPKD.
dc.format.extent146 pagesen_US
dc.language.isoen_USen_US
dc.publisherUniversity of Kansasen_US
dc.rightsThis item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.en_US
dc.subjectGenetics
dc.subjectMolecular biology
dc.subjectDevelopmental biology
dc.subjectCell proliferation
dc.subjectCux1
dc.subjectKidney development
dc.subjectP27
dc.subjectPolycystic kidney disease
dc.titleRegulation of cell proliferation in autosomal dominant polycystic kidney disease
dc.typeDissertationen_US
dc.contributor.cmtememberAbrahamson, Dale
dc.contributor.cmtememberBlanco, Gustavo
dc.contributor.cmtememberRongish, Brenda
dc.contributor.cmtememberWright, Douglas
dc.thesis.degreeDisciplineAnatomy & Cell Biology
dc.thesis.degreeLevelPh.D.
kusw.oastatusna
kusw.oapolicyThis item does not meet KU Open Access policy criteria.
dc.rights.accessrightsopenAccessen_US


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