This Project explores the molecular genetics of anti-neutrophil cytoplasmic autoantibody (ANCA) glomerulonephritis. The objective of this proposal is to identify genes and their controlling factors that are permissive for or modify the expression of ANCA glomerulonephritis for elucidation of the etiology and therapy of this disorder. In the current Program Project, we observed aberrant expression of proteinase 3 (PR3) and myeloperoxidase (MPO) mRNA in mature leukocytes of patients with ANCA glomerulonephritis. ANCA activate neutrophils and monocytes by interacting with their target antigens on the surface of these cells. Understanding the mechanism of MPO and PR3 gene expression in active ANCA glomerulonephritis is a critical key to the disease pathogenesis.
Specific Aim 1 hypothesizes that there are identifiable factors permitting aberrant expression of message for PR3 and MPO, resulting in over-expression of target antigens in leukocytes from patients with active ANCA glomerulonephritis. We have accumulated transcriptional microarray data on patients with ANCA glomerulonephritis and other autoimmune diseases, and have identified a number of critically important genes. Using a candidate gene and then a whole genome scan approach, Specific Aim 2 hypothesizes that there are genes permissive for, or that modify the expression of ANCA glomerulonephritis.
This aim follows logically from the transcriptional microarray studies. Using iterative bio informatics, we identified several genes that correlate with ANCA small vessel vasculitis disease activity, some of which have been confirmed with real time rtPCR, and we are uncovering still others.
Specific Aim 3 hypothesizes that the leukocyte mRNA signatures for a restricted number of leukocyte genes will provide a more sensitive and specific strategy for defining clinical disease relapse and remission than any existing clinically available parameter. We are ready to embark on an approach that places candidate """"""""genes on a stick"""""""" to prospectively sample patient leukocyte gene expression as markers of clinical disease activity. The clinical exigency is great, for there is no existing clinical marker of disease activity, including ANCA titers, that reliably answers the critical conundrum for doctors and their patients with ANCA glomerulonephritis, or any autoimmune disease-that is, """"""""When can I stop and when do I need to restart life-saving yet life-threatening immunosuppressive therapy?""""""""

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK058335-10
Application #
7911818
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
10
Fiscal Year
2009
Total Cost
$253,248
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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
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Weiner, Maria; Bjørneklett, Rune; Hrušková, Zdenka et al. (2018) Proteinase-3 and myeloperoxidase serotype in relation to demographic factors and geographic distribution in anti-neutrophil cytoplasmic antibody-associated glomerulonephritis. Nephrol Dial Transplant :
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Jones, Britta E; Yang, Jiajin; Muthigi, Akhil et al. (2017) Gene-Specific DNA Methylation Changes Predict Remission in Patients with ANCA-Associated Vasculitis. J Am Soc Nephrol 28:1175-1187
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