The aim of this Program Project is to identify the genes and pathways responsible for development of familial IgA nephropathy (IgAN). The approaches in the 3 Projects will refine the genetic location of the recently identified disease locus on chromosome 6q22-23 (IGAM1), evaluate the biosynthesis of IgA1 and its glycosylation in B lymphocytes, and assess the pathogenic role of cir5cuylating immune complexes with undergalactosylated IgA1. These studies require many patients with well- defined clinical phenotypes and appropriate family members and controls. Patients with familial or sporadic IgAN, Henoch-Schonlein purpura (HSP), family members, and non-IgAN disease- and healthy control subjects in a 7-stage catchment area will be enrolled. To provide clinical resources and statistical support for the 3 Projects, Core A will collect blood and urine samples (and residual renal tissue if biopsy done within 30 days), compile clinical and laboratory data in aq centralized database, and correlate laboratory and clinical data.
The Specific Aims of Core A are: 1. Enroll 1515 subjects for the 3 Projects: 20 pedigrees with 50 familial IgAN/HSP patients and about 150 of their family members, 150 Caucasian sporadic IgAN patients and 375 of their family members, 50 HSP patients and 125 of their family members, 50 African-American IgAN patients and 200 of their family members, 65 non-IgAN disease- controls, and 200 Caucasian and 100 African-American healthy controls. 2. Establish and manage the computerized database for the entire Program Project: (a) compile the demographic, clinical, laboratory, histopathologic, and genetic data; (b) coordinate and manage statistical analyses to ensure investigators have ready access to statistical consultation and support; (c) provide statistical expertise including sample-size estimation and power calculations, randomization procedures, and design of data collection forms; and (d) perform interim reviews and final analyses. 3. Coordinate collection and distribution of blood and urine samples from patients and controls, and establish immortalized cell lines from selected subjects. 4. Perform detailed histologic analyses of residual renal tissue of newly biopsied IgAN/HSP and non-IgAN glomerulonephritis patients from whom blood and urine samples will be obtained for contemporaneous in vitro studies. The findings from this Program Project will substantially increase the understanding of the pathogenesis of a common renal disease and may be the foundation for future development of a disease-specific therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
1P01DK061525-01
Application #
6555236
Study Section
Special Emphasis Panel (ZDK1)
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2002
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Tamouza, Houda; Chemouny, Jonathan M; Raskova Kafkova, Leona et al. (2012) The IgA1 immune complex-mediated activation of the MAPK/ERK kinase pathway in mesangial cells is associated with glomerular damage in IgA nephropathy. Kidney Int 82:1284-96
Novak, Jan; Raskova Kafkova, Leona; Suzuki, Hitoshi et al. (2011) IgA1 immune complexes from pediatric patients with IgA nephropathy activate cultured human mesangial cells. Nephrol Dial Transplant 26:3451-7
Camilla, Roberta; Suzuki, Hitoshi; Daprà, Valentina et al. (2011) Oxidative stress and galactose-deficient IgA1 as markers of progression in IgA nephropathy. Clin J Am Soc Nephrol 6:1903-11
Gomes, Michelle M; Suzuki, Hitoshi; Brooks, Monica T et al. (2010) Recognition of galactose-deficient O-glycans in the hinge region of IgA1 by N-acetylgalactosamine-specific snail lectins: a comparative binding study. Biochemistry 49:5671-82
Good, David M; Zürbig, Petra; Argilés, Angel et al. (2010) Naturally occurring human urinary peptides for use in diagnosis of chronic kidney disease. Mol Cell Proteomics 9:2424-37
Lavigne, K A; Woodford, S Y; Barker, C V et al. (2010) Familial IgA nephropathy in southeastern Kentucky. Clin Nephrol 73:115-21
Hastings, M Colleen; Moldoveanu, Zina; Julian, Bruce A et al. (2010) Galactose-deficient IgA1 in African Americans with IgA nephropathy: serum levels and heritability. Clin J Am Soc Nephrol 5:2069-74
Suzuki, Hitoshi; Fan, Run; Zhang, Zhixin et al. (2009) Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin Invest 119:1668-77
Mischak, Harald; Coon, Joshua J; Novak, Jan et al. (2009) Capillary electrophoresis-mass spectrometry as a powerful tool in biomarker discovery and clinical diagnosis: an update of recent developments. Mass Spectrom Rev 28:703-24

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