The application requests funding with the specific intent of developing an independent research program by the principal investigator. The applicant has been pursuing basic science research in the areas of T cell immunology and pathogenesis of lupus (SLE) for the past four years. The proposal is an extension of the applicant's current research on monocyte/macrophage (M theta) apoptosis. Hypothesis: Apoptosis-inducing molecules mediate the autologous monocyte/M theta killing caused by CD4+ lupus T cells. Target cell killing by this mechanism can lead to the generation of autoantibodies.
Specific aims : To determine the pathways involved in monocyte/M theta apoptosis induced by lupusCD4+ T cells. The applicant will test whether it's possible to inhibit the development of autoimmunity in an SLE animal model, by blocking the apoptotic pathways involved in monocyte/M theta killing by autoreactive CD4+ T cells. The role of macrophage apoptosis in triggering or augmenting autoimmunity will also be investigated. Methods: a) Measurement of cell surface expression of death-receptor ligands on SLE and control T cells by flow cytometry. b) With cytotoxicity assays, determine whether these apoptotic pathways are functional in SLE monocytes/M theta and whether blocking these molecules can inhibit the autologous monocyte/M theta killing by SLE T cells. c) Given the redundancy of the pathways involved in M theta cytotoxicity, the applicant will test, in vitro, if inhibiting the death signals downstream of the death receptors (FADD, caspases, FLIP) is sufficient to inhibit monocyte/M theta apoptosis induced by these ligands. d) In vivo studies will try to characterize whether the blockade on monocyte/macrophage death-receptor ligands by monoclonal antibodies or fusion proteins, can inhibit the development of murine SLE, and whether the elimination of tissue macrophages; per se (with clodronate liposomes in vivo) is sufficient to induce autoimmunity in an animal model. The results of the studies proposed might identify potential mechanisms involved in the generation of autoantigens in SLE. These could lead into the development of therapeutic interventions designed to reverse these abnormalities and abrogate or block the onset and severity of this disease. The sponsor and the institution are committed to contributing protected time, career development and resources to the applicant.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR048235-04
Application #
6924545
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Gretz, Elizabeth
Project Start
2002-09-20
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$128,520
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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