This proposes to study signal transduction regulation of leukocyte integrin molecules. The current application grew out of the realization that a body of mostly forgotten work about the effects of MTB on phagocytic cells, dating back as far as 1949, could now be reinterpreted at the molecular level based on more recent understanding of the existence and function of integrin proteins. In the last year, the candidate has acquired substantial preliminary data in support of her hypotheses as follows: (1) key aspects of the granulomatous response to MTB are mediated by integrin molecules; (2) virulent strains of MTB may impair integrin response; and (3) modulators of integrin activation influence the outcome of MTB infection.
The specific aims follow from the hypotheses: (1) to study signalling mechanisms and integrin phosphorylation changes during activation of monocyte aggregation, MTB phagocytosis and multinucleated giant cell formation; (2) to compare results of Aim 1 using monocytes and alveolar macrophages from men and women with or without AIDS, and with or without tuberculosis; (3) to test the ability of MTB or a virulent strain lipid, sulfolipid 1, to inhibit integrin function; and (4) to determine baseline monocyte functions in individuals with various stages of immune compromise, and to test the potential enhancing effects of signalling regulators and integrin antibodies.
| Merrill, J T; Shen, C; Schreibman, D et al. (1997) Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: a mechanism for methotrexate-induced nodulosis in rheumatoid arthritis. Arthritis Rheum 40:1308-15 |
