Abstract

Glomerular basement membrane (GBM) function is altered in three notable human diseases that affect the kidneys: Goodpasture syndrome/anti-GBM nephritis, Alport syndrome and diabetes mellitus. The molecular defects underlying Goodpasture and Alport syndromes have been linked to type IV collagen, the major constituent of GBM. These advances raise many unanswered questions about the structure, function and role of these chains in the pathogenesis of Goodpasture and Alport syndromes and diabetic renal disease. Understanding structure and assembly of normal type IV collagen is a prerequisite for delineating pathogenic mechanisms. The central thrust of this renewal proposal is to express truncated chains and NC1 domains in eukaryotic cells for elucidation of 1) assembly mechanisms of human type IV collagen suprastructures and 2) pathogenic mechanisms of how mutations in these chains cause defective assembly.
The specific aims are:
Aim 1 : To characterize type IV collagen of normal human GBM with respect to composition, organization and crosslinking of chains.
Aim 2 : To elucidate discriminatory molecular interactions that code for the assembly of human type IV collagen suprastructures.
Aim 3 : To elucidate how genetic mutations cause defective assembly of type IV collagen suprastructures.
Aim 4 : To elucidate the epitope structure for Goodpasture autoantibodies.
Aim 5 : To sub-localize the epitope for the Alport alloantibodies within the NC1 domain.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK018381-26
Application #
2905205
Study Section
Pathology A Study Section (PTHA)
Program Officer
Ketchum, Christian J
Project Start
1986-09-01
Project End
2000-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
26
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Kansas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160

  Publications

McCall, A Scott; Bhave, Gautam; Pedchenko, Vadim et al. (2018) Inhibitory Anti-Peroxidasin Antibodies in Pulmonary-Renal Syndromes. J Am Soc Nephrol 29:2619-2625
Pedchenko, Vadim; Kitching, A Richard; Hudson, Billy G (2018) Goodpasture's autoimmune disease - A collagen IV disorder. Matrix Biol 71-72:240-249
Brown, Kyle L; Banerjee, Surajit; Feigley, Andrew et al. (2018) Salt-bridge modulates differential calcium-mediated ligand binding to integrin ?1- and ?2-I domains. Sci Rep 8:2916
Fidler, Aaron L; Boudko, Sergei P; Rokas, Antonis et al. (2018) The triple helix of collagens - an ancient protein structure that enabled animal multicellularity and tissue evolution. J Cell Sci 131:
Boudko, Sergei P; Danylevych, Neonila; Hudson, Billy G et al. (2018) Basement membrane collagen IV: Isolation of functional domains. Methods Cell Biol 143:171-185
Xie, Li-Jun; Cui, Zhao; Chen, Fang-Jin et al. (2017) The susceptible HLA class II alleles and their presenting epitope(s) in Goodpasture's disease. Immunology 151:395-404
Ooi, Joshua D; Petersen, Jan; Tan, Yu H et al. (2017) Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. Nature 545:243-247
Jones-Paris, Celestial R; Paria, Sayan; Berg, Taloa et al. (2017) Embryo implantation triggers dynamic spatiotemporal expression of the basement membrane toolkit during uterine reprogramming. Matrix Biol 57-58:347-365
Fidler, Aaron L; Darris, Carl E; Chetyrkin, Sergei V et al. (2017) Collagen IV and basement membrane at the evolutionary dawn of metazoan tissues. Elife 6:
Cui, Zhao; Zhao, Ming-Hui; Jia, Xiao-Yu et al. (2016) Antibodies to ?5 chain of collagen IV are pathogenic in Goodpasture's disease. J Autoimmun 70:1-11

Showing the most recent 10 out of 89 publications