The complement system plays an important role in inflammation in host defenses against infection and immunopathology. Based on recent studies, the complement system seems also to be involved in specific immunity, energy metabolism and reproductive biology. The major goal of this proposal is to define the cellular specificity of complement expression as a function of development (prenatal and postnatal), tissue site and systemic Or local acute phase stimulus with probes corresponding to specific complement genes and with immunohistochemical methods. The mechanisms responsible for cellular specific expression, developmental regulation, the response to acute phase induced cytokines and the counterregulation of this effect will be ascertained. For these studies, specific cis and trans control elements necessary and sufficient for the response(s) will be defined. The cell biology of translational and posttranslational regulation will be explored as part of this objective. An ability to selectively modulate inflammation in a tissue specific way depends on understanding these mechanisms. Models of inflammation including mice that spontaneously develop """"""""autoimmune"""""""" disease as well as animals undergoing an acute phase response will be studied. These and normal mice of different stages in development are studied at a cellular level with molecular biological and immunochemical methods. Pertinent cell lines of epithelial origin are utilized for pursuing molecular mechanisms. Control of human disorders such as rheumatoid arthritis, systemic lupus erythematosus, etc., represent obvious disease targets for the proposed research efforts. However, recent data showing, for example, a role of complement in producing tissue injury following ischemia suggests a broader implication of the proposed studies.
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