Alport syndrome results from mutations in either the type IV collagen COL4A3, COL4A4, or COL4A5 genes. Pathology includes a juvenile onset progressive glomerulonephritis with glomerular basement membrane (GBM) rarefication and expansions of the mesangial matrix, culminating in death due to renal failure. A gene-knockout mouse model for Alport syndrome was produced in this laboratory, the renal pathology of which is remarkably similar to that observed in humans. Deposition of specific extracellular matrix proteins in the GBM follows course with basement membrane rarefication. This must be due to changes in their synthesis and/or turnover..
The aims of this proposal focus on clarifying the role of synthesis and degradation of basement membrane collagens and associated proteins in Aport GBM disease progression. The possible role of integrin receptors, transforming growth factor beta 1 (TGF-beta1), and metalloproteinases (and their inhibitors) will be explored. Quantitative analysis (employing material from isolated glomeruli) will be used to determine relative levels of specific mRNAs (by norther blot) and their corresponding proteins (by western blot). In situ hybridization studies will determine which glomerular cell types synthesize these proteins. Observations with potential mechanistic significance will be tested using human renal biopsy tissues from normal and Alport patients. Whether TGF-beta1 or proteinuria is linked to induction of genes encoding extracellular matrix molecules will be probed using a combination approach of TGF-beta type I and II receptor inhibitor (FK506) molecules will be probed using a combination approach of TGF-beta1. A double knockout of the COL4A3 and integrin alpha1 chain has been produced, and shows a marked reduction in the rate of Alport renal disease progression. The molecular mechanism of this surprising effect will be explored. Identification of the molecular mechanisms underlying the imbalance in GBM homeostasis in Alport syndrome may reveal potential targets for pharmacologic intervention.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine B Study Section (GMB)
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Flessner, Michael Francis
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Father Flanagan's Boys' Home
Boys Town
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Cosgrove, Dominic; Liu, Shiguang (2017) Collagen IV diseases: A focus on the glomerular basement membrane in Alport syndrome. Matrix Biol 57-58:45-54
Meehan, Daniel T; Delimont, Duane; Dufek, Brianna et al. (2016) Endothelin-1 mediated induction of extracellular matrix genes in strial marginal cells underlies strial pathology in Alport mice. Hear Res 341:100-108
Dufek, Brianna; Meehan, Daniel T; Delimont, Duane et al. (2016) Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease. Kidney Int 90:300-310
Delimont, Duane; Dufek, Brianna M; Meehan, Daniel T et al. (2014) Laminin ?2-mediated focal adhesion kinase activation triggers Alport glomerular pathogenesis. PLoS One 9:e99083
Tian, Mei; Wang, Weimin; Delimont, Duane et al. (2014) Photoreceptors in whirler mice show defective transducin translocation and are susceptible to short-term light/dark changes-induced degeneration. Exp Eye Res 118:145-53
Zallocchi, Marisa; Johnson, Brianna M; Meehan, Daniel T et al. (2013) ?1?1 integrin/Rac1-dependent mesangial invasion of glomerular capillaries in Alport syndrome. Am J Pathol 183:1269-1280
Tian, Mei; Zallocchi, Marisa; Wang, Weimin et al. (2013) Light-induced translocation of RGS9-1 and G?5L in mouse rod photoreceptors. PLoS One 8:e58832
Cosgrove, Dominic (2012) Glomerular pathology in Alport syndrome: a molecular perspective. Pediatr Nephrol 27:885-90
Peng, You-Wei; Zallocchi, Marisa; Wang, Wei-Min et al. (2011) Moderate light-induced degeneration of rod photoreceptors with delayed transducin translocation in shaker1 mice. Invest Ophthalmol Vis Sci 52:6421-7
Dennis, Jameel; Meehan, Daniel T; Delimont, Duane et al. (2010) Collagen XIII induced in vascular endothelium mediates alpha1beta1 integrin-dependent transmigration of monocytes in renal fibrosis. Am J Pathol 177:2527-40

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