Abstract

Nuclear factor-kappaB (NF-kappaB) plays a key role in the expression of many genes central to the rheumatic diseases. Participation of this transcription factor in the expression of IL-1b in monocytes, and ICAM-l, TNF-alpha and IL-6 in rheumatoid synoviocytes has been demonstrated. Also, the transcription factor regulates inducible expression of the cell adhesion molecules Eselectin, VCAM-l and ICAM-l in vascular endothelial cells. A primary goal of my laboratory is to develop intra-articular gene therapy for rheumatoid arthritis using a dominant negative adenoviral IkappaB kinase (DN IKK2) construct to block NF-kappaB activation. In vitro studies demonstrated that IKK2 is the primary pathway that regulates synoviocyte production of cytokines like IL-6 and IL-8. In vivo studies have shown that suppression of IKK2 using intra-articular DN IKK2 inhibits clinical arthritis in the adjuvant arthritis model in rats. In preparation for human studies with DN IKK2, we propose to determine the distribution and duration of expression of IKK2 construct in joints after direct intra- articular gene therapy. We will then evaluate the toxicology of the adenoviral construct in rats.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Comprehensive Center (P60)
Project #
5P60AR040770-09
Application #
6310392
Study Section
Special Emphasis Panel (ZAR1-MHG-B (J1))
Project Start
1991-08-01
Project End
2001-02-28
Budget Start
Budget End
Support Year
9
Fiscal Year
2000
Total Cost
$112,459
Indirect Cost

  Institution

Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Malcarne, Vanessa L; Hansdottir, Ingunn; McKinney, Ann et al. (2007) Medical signs and symptoms associated with disability, pain, and psychosocial adjustment in systemic sclerosis. J Rheumatol 34:359-67
Leake, John A D; Albani, Salvatore; Kao, Annie S et al. (2004) Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features. Pediatr Infect Dis J 23:756-64
Meyer, Markus; Belke, Darrell D; Trost, Susanne U et al. (2004) A recombinant antibody increases cardiac contractility by mimicking phospholamban phosphorylation. FASEB J 18:1312-4
Groessl, Erik J; Kaplan, Robert M; Cronan, Terry A (2003) Quality of well-being in older people with osteoarthritis. Arthritis Rheum 49:23-8
Kaplan, Robert M (2003) The significance of quality of life in health care. Qual Life Res 12 Suppl 1:3-16
Johnson, Kristen; Goding, James; Van Etten, Deborah et al. (2003) Linked deficiencies in extracellular PP(i) and osteopontin mediate pathologic calcification associated with defective PC-1 and ANK expression. J Bone Miner Res 18:994-1004
La Cava, Antonio; Massa, Margherita; Mendivil, Alberto et al. (2002) Genetic immunization maps T cell (auto)immune responses to self antigens homologous to exogenous proteins. Autoimmunity 35:105-10
Prakken, Berent J; Roord, Sarah; van Kooten, Peter J S et al. (2002) Inhibition of adjuvant-induced arthritis by interleukin-10-driven regulatory cells induced via nasal administration of a peptide analog of an arthritis-related heat-shock protein 60 T cell epitope. Arthritis Rheum 46:1937-46
Kaplan, Robert M (2002) Quality of life: an outcomes perspective. Arch Phys Med Rehabil 83:S44-50
Silverman, Gregg J; Goodyear, Carl S (2002) A model B-cell superantigen and the immunobiology of B lymphocytes. Clin Immunol 102:117-34

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