The theme of this grant is modulation of pathogenic and therapeutic mechanisms in rheumatoid arthritis (RA). Projects 1, 2, and 3 will focus on T cell-macrophage and T cell-synovial cell interactions and cytokine-synovial cell interactions in the generation of synovial lesions of RA. Using new monoclonal antibodies, new assay systems for the study of molecules involved in T cell interaction with RA synovial microenvironment cells, and measurements of cytokine (e.g. IL-1 and TNF) effect on synovial microenvironment cells and cytokine messenger RNA production using Northern blot and in situ hybridization analysis, the specific mechanisms and molecules in T cell-synovial microenvironment cell interactions and their sequelae will be studied. In addition cellular and molecular events associated with synovial lining cell activation to proliferation on inflammatory cytokine release with be studied. Project 4 will investigate B cell auto-antibody production in Sjogren's Syndrome and RA using cloned Ro and La recombinant autoantigens. Project 5 explores the pathogenesis of the MRL mouse model of arthritis using many of the same techniques and concepts discussed in projects 1, 2, and 3. Project 6 uses proven and innovative modalities of pain modification to alter RA patients' response to chronic pain -- thereby modifying a pathogenic mechanism (chronic pain) that is a major cause of morbidity in RA. Taken together, the work proposed in this SCOR grant represents a multidisciplinary effort to use innovative and novel approaches to modify joint inflammation, bone loss, and chronic pain in RA. By understanding basic mechanisms of pathogenesis of RA at the molecular, cellular, metabolic, and neuropsychiatric levels, hopefully novel therapies capable of modifying, and ultimately abrogating, the pathogenic mechanisms that lead to morbidity and mortality in RA can be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
1P50AR039162-01
Application #
3105133
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1987-09-30
Project End
1992-08-31
Budget Start
1987-09-30
Budget End
1988-08-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Weinberg, J Brice; Lang, Thomas; Wilkinson, William E et al. (2006) Serum, urinary, and salivary nitric oxide in rheumatoid arthritis: complexities of interpreting nitric oxide measures. Arthritis Res Ther 8:R140
Perkins, Douglas J; Hittner, James B; Mwaikambo, Esther D et al. (2005) Impaired systemic production of prostaglandin E2 in children with cerebral malaria. J Infect Dis 191:1548-57
Elliott, Margaret K; Jarmi, Tambi; Ruiz, Phil et al. (2004) Effects of complement factor D deficiency on the renal disease of MRL/lpr mice. Kidney Int 65:129-38
Douglas, Glenn; Reilly, Christopher; Dooley, Mary Anne et al. (2004) Angiotensin-converting enzyme (insertion/deletion) and endothelial nitric oxide synthase polymorphisms in patients with systemic lupus erythematosus. J Rheumatol 31:1756-62
Erickson, G R; Northrup, D L; Guilak, F (2003) Hypo-osmotic stress induces calcium-dependent actin reorganization in articular chondrocytes. Osteoarthritis Cartilage 11:187-97
Oates, Jim C; Levesque, Marc C; Hobbs, Maurine R et al. (2003) Nitric oxide synthase 2 promoter polymorphisms and systemic lupus erythematosus in african-americans. J Rheumatol 30:60-7
Fermor, B; Weinberg, J B; Pisetsky, D S et al. (2002) Induction of cyclooxygenase-2 by mechanical stress through a nitric oxide-regulated pathway. Osteoarthritis Cartilage 10:792-8
Fong, Alan M; Premont, Richard T; Richardson, Ricardo M et al. (2002) Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice. Proc Natl Acad Sci U S A 99:7478-83
Guilak, Farshid; Erickson, Geoffrey R; Ting-Beall, H Ping (2002) The effects of osmotic stress on the viscoelastic and physical properties of articular chondrocytes. Biophys J 82:720-7
Cernanec, Julie; Guilak, Farshid; Weinberg, J Brice et al. (2002) Influence of hypoxia and reoxygenation on cytokine-induced production of proinflammatory mediators in articular cartilage. Arthritis Rheum 46:968-75

Showing the most recent 10 out of 152 publications