Glomerulonephritis and small vessel vasculitis caused by antl-neutrophil cytoplasmic autoantibodies (ANCA) is the most common cause for rapidly progressive glomerulonephritis, which frequently leads to end stage renal disease If not diagnosed quickly and treated appropriately. This Project will use mouse models that closely resemble human ANCA disease to advance understanding of the pathogenesis of this autoimmune inflammatory process with the goal of translating this knowledge Into better treatment of patients.
Specific Aim1 will Investigate the role of complement activation and Fcy receptor engagement in mediating ANCA disease. Complement studies will include evaluation of the effects of a novel small molecule inhibitor of human C5a receptor in mice genetically engineered to express human C5a receptor. Involvement of both activating Fcy receptors In Inducing Inflammation, as well as inhibitory Fcy receptors In modulating inflammation will be studies.
Specific Aim 2 seeks to create models of ANCA disease directed at additional autoantigens to more closely parallel human disease. The current model is induced by antibodies to myeloperoxidase.
This Aim will pursue models induced by antibodies to proteinase 3 and lysosomal membrane protein-2;and also will test the ability of complementary (anti-sense) peptides to induce pathogenic autoantibody responses to sense peptides.
Specific Aim 3 will probe the genetic basis for variations in ANCA disease between different strains of mice, which mimics the marked variations in ANCA disease among patients. These studies will utilize a robust new method for genetic research in mice, the Collaborative Cross, which will illustrate the power of this approach for studying kidney diseases. Genes (and their protein products) that are found to influence disease in this animal model will be likely candidates for markers of disease activity and outcome in patients, and might also be logical targets for novel therapies. Investigation of inflammatory and immunologic processes in this animal model will provide insights into other renal and nonrenal inflammatory and autoimmune diseases. The goal of the research is to translate new knowledge from this model into improved outcomes for patients with this aggressive form of kidney disease.

Public Health Relevance

Antlneutrophil cytoplasmic autoantibodies (ANCA) are antibodies that activate inflammatory cells (neutrophils) in the blood causing them to attack small blood vessels in many organs resulting in vascular inflammation (vasculitis). This inflammation often involved the small filtering units of the kidney (glomeruli) resulting in glomerulonephritis. The research in this project will study ANCA disease in experimental animals with the goal of improving treatment for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK058335-15
Application #
8707432
Study Section
Special Emphasis Panel (ZDK1-GRB-R)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
15
Fiscal Year
2014
Total Cost
$334,644
Indirect Cost
$107,915
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Mariani, Laura H; Pendergraft 3rd, William F; Kretzler, Matthias (2016) Defining Glomerular Disease in Mechanistic Terms: Implementing an Integrative Biology Approach in Nephrology. Clin J Am Soc Nephrol 11:2054-2060
Yang, Jiajin; Ge, Heng; Poulton, Caroline J et al. (2016) Histone modification signature at myeloperoxidase and proteinase 3 in patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis. Clin Epigenetics 8:85
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Bunch, Donna O; Mendoza, Carmen E; Aybar, Lydia T et al. (2015) Gleaning relapse risk from B cell phenotype: decreased CD5+ B cells portend a shorter time to relapse after B cell depletion in patients with ANCA-associated vasculitis. Ann Rheum Dis 74:1784-6

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