End-stage renal disease (ESRD) is a chronic condition that affects approximately 700,000 persons each year (worldwide), at an estimated cost exceeding $20 billion. It is generally agreed that once chronic renal insufficiency is established, renal disease is almost always progressive. The clinical course of most renal disease can be separated into the etiologic or initiation stage, which is followed by the progression of pathogenetic stage. Although the causes vary widely, recent studies indicate that the progression component that culminates in ESRD shares many features in common among diverse renal disorders. The unifying theme of this Program Project is the exploration of molecular mechanisms underlying the progression of diseases of different etiologies to a common outcome, end-stage renal failure. Three renal disease with clear-cut etiologies (Alport syndrome, autosomal dominant polycystic kidney disease (ADPKD) and diabetic nephropathy) were selected to pursue the overall research objectives. The Program Project is composed of four scientific projects that address specific elements of disease progression, and a supportive administrative core. Project 1 will test the hypothesis that the progression to ESRD in X-linked Alport syndrome evolves from a congenital malformation of the glomerular basement membrane (GBM) which involves COL4A5 gene mutations that arrest a developmental switch from an immature alpha1(IV)/alpha2(IV) collagen network to a mature alpha3(IV)/alpha4(IV)/alpha5(IV) network, and the persistence of this immature network predisposes the GBM to proteolytic degradation. Project 2 will test the hypothesis that the functions of polycystin-1 and polycystin-2, which are mutated in ADPKD, are mediated by signal transduction, and as such, that these proteins are substrates for phosphorylation, and that phosphorylation of these proteins affects their interactions with each other and with other signal transduction proteins, in particular Galpha subunits of heterotrimeric G-proteins. Project 3 will test the hypothesis that cyst activating factor, a novel neutral lipid that accumulates in cysts of ADPKD patients, promotes fluid secretion and cellular proliferation by cyst epithelial cells, and induces chemokine, cytokine and metalloproteinase production in renal epithelial cells and macrophages. The long term goal is for the research to contribute to novel treatments to slow or arrest the progression of these renal disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
1P01DK053763-01
Application #
2557917
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (J1))
Project Start
1998-06-25
Project End
2003-05-31
Budget Start
1998-06-25
Budget End
1999-05-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Kansas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Putnam, William C; Swenson, Sarah M; Reif, Gail A et al. (2007) Identification of a forskolin-like molecule in human renal cysts. J Am Soc Nephrol 18:934-43
Puri, Sanjeev; Rodova, Marianna; Islam, M Rafiq et al. (2006) Ets factors regulate the polycystic kidney disease-1 promoter. Biochem Biophys Res Commun 342:1005-13
Harvey, Scott J; Perry, Julie; Zheng, Keqin et al. (2006) Sequential expression of type IV collagen networks: testis as a model and relevance to spermatogenesis. Am J Pathol 168:1587-97
Zheng, Keqin; Perry, Julie; Harvey, Scott J et al. (2005) Regulation of collagen type IV genes is organ-specific: evidence from a canine model of Alport syndrome. Kidney Int 68:2121-30
Yamaguchi, Tamio; Wallace, Darren P; Magenheimer, Brenda S et al. (2004) Calcium restriction allows cAMP activation of the B-Raf/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype. J Biol Chem 279:40419-30
Puri, Sanjeev; Magenheimer, Brenda S; Maser, Robin L et al. (2004) Polycystin-1 activates the calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway. J Biol Chem 279:55455-64
Belibi, Franck A; Reif, Gail; Wallace, Darren P et al. (2004) Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells. Kidney Int 66:964-73
Rodova, Marianna; Islam, M Rafiq; Peterson, Kenneth R et al. (2003) Remarkable sequence conservation of the last intron in the PKD1 gene. Mol Biol Evol 20:1669-74
Borza, Dorin-Bogdan; Neilson, Eric G; Hudson, Billy G (2003) Pathogenesis of Goodpasture syndrome: a molecular perspective. Semin Nephrol 23:522-31
Harvey, Scott J; Zheng, Keqin; Jefferson, Barbara et al. (2003) Transfer of the alpha 5(IV) collagen chain gene to smooth muscle restores in vivo expression of the alpha 6(IV) collagen chain in a canine model of Alport syndrome. Am J Pathol 162:873-85

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