Polycystic kidney disease (PKD) is the most common inherited disorder leading to chronic kidney disease and renal failure. Human pedigrees and rodent models have led to cloning of genes linked to PKD. Characterization of two mutant mouse strains, kat and kat2J, both of which develop progressive PKD, has linked Nek1 (Aspergillus NimA-related kinase) to the pathogenesis of PKD. To date, we have shown that Nek1 is involved early in DNA damage response and that cells without functional Nek1 are sensitive to ionizing radiation. Here, we propose that Nek1 is involved fundamentally in the pathogenesis of several forms of PKD, including human autosomal dominant PKD, as a factor that modifies disease progression in the setting of superimposed ischemic or genotoxic stress. Renal tubular cells in polycystic kidneys suffer from aberrant DNA damage repair responses, which result in both cyst- initiating, second-hit mutations to genes like PKD1 and PKD2, if the damage is passed on to proliferating daughter cells. They also undergo aberrant apoptosis in excessive numbers when the DNA damage is severe and irreparable. In this proposal, we will explore the roles of Nek1 protein kinase in ischemic injury, DNA damage, and apoptosis.
In Aim 1, we will examine the expression of Nek1 in response to ischemia-reperfusion tubular injury, the effects of this injury on the progression of PKD in kat2J mice, and mutation frequency and spectrum induced by ischemic-oxidative injury in kat2J mice.
In Aim 2, we will explore the roles of Nek1 in the DNA damage response and DNA repair. We will systematically determine how Nek1 is involved in sensing and responding DNA damage, by carefully dissecting potential upstream regulators and downstream effectors of Nek1, and by identification of key potential substrates of Nek1 involved in the DNA damage/repair pathway.
In Aim 3, we will examine the detailed mechanisms by which Nek1 affects renal tubular cell apoptosis after injury, based on our evidence that Nek1 is crucial for regulating the VDAC component of the mitochondrial transition pore channel, which initiates the apoptotic caspase cascade when open. Our studies will provide novel insight into the molecular pathogenesis of PKD. They will help explain why cysts progress at different rates and how therapies to slow the progression of PKD can be designed rationally.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067339-06
Application #
7780012
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rasooly, Rebekah S
Project Start
2006-03-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
6
Fiscal Year
2010
Total Cost
$236,382
Indirect Cost
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Chen, Yumay; Chen, Chi-Fen; Polci, Rosaria et al. (2014) Increased Nek1 expression in renal cell carcinoma cells is associated with decreased sensitivity to DNA-damaging treatment. Oncotarget 5:4283-94
Chen, Yumay; Chiang, Huai-Chin; Litchfield, Patricia et al. (2014) Expression of Nek1 during kidney development and cyst formation in multiple nephron segments in the Nek1-deficient kat2J mouse model of polycystic kidney disease. J Biomed Sci 21:63
Chen, Yumay; Chen, Chi-Fen; Chiang, Huai-Chin et al. (2011) Mutation of NIMA-related kinase 1 (NEK1) leads to chromosome instability. Mol Cancer 10:5
Chen, Yumay; Chen, Chi-Fen; Riley, Daniel J et al. (2011) Nek1 kinase functions in DNA damage response and checkpoint control through a pathway independent of ATM and ATR. Cell Cycle 10:655-63
Chen, Yumay; Gaczynska, Maria; Osmulski, Pawel et al. (2010) Phosphorylation by Nek1 regulates opening and closing of voltage dependent anion channel 1. Biochem Biophys Res Commun 394:798-803
Chen, Yumay; Craigen, William J; Riley, Daniel J (2009) Nek1 regulates cell death and mitochondrial membrane permeability through phosphorylation of VDAC1. Cell Cycle 8:257-67
Chen, Yumay; Chen, Phang-Lang; Chen, Chi-Fen et al. (2008) Never-in-mitosis related kinase 1 functions in DNA damage response and checkpoint control. Cell Cycle 7:3194-201