The objectives of this program are to elucidate complex molecular and cellular events that are common to mechanisms underlying diverse immunological diseases and that overlap with molecular and cellular mechanisms of host defense against infections and malignancies. It is our aim to gain an understanding of the process of inflammation and of certain host defense mechanisms at the molecular level. We will address the biochemistry and molecular biology of the complement and the Hageman factor systems. We will conduct biochemical studies of the specific and non-specific activation of these systems. We will explore the pathophysiologic effects of activation products in experimental animals and on isolated cells in vitro. The role of complement fragments in mediating phagocytosis will be determined. Cell surface receptors specific for complement proteins will be isolated and characterized. We will investigate the changes in the molecular organization of the plasma membrane of inflammatory cells that are associated with such cellular responses as phagocytosis, exocytosis and chemotaxis. The structure and function of the membrane attack complex through which complement kills cells will be elaborated. The possibility will be explored whether complement-like molecules are synthesized and utilized by cytotoxic lymphocytes. A comparative study will be performed of turnover and tissue deposition of proteins of the Hageman factor and complement systems in experimental inflammatory disease. Because of its central position in molecular immunology, the covalent structure of C3 will be tackled.
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