One of the major biological consequences of complement activation is the generation of three small cationic peptides C3a, C4a, and C5a, collectively referred to as complement anaphylatoxins. The complement anaphylatoxins are potent proinflammatory molecules that mediate numerous biological functions by binding to seven transmembrane G-protein coupled receptors expressed on specific target cells. The acute and chronic overproduction of complement anaphylatoxin peptides is considered to be a major contributor to the pathogenesis of numerous diseases, including rheumatoid arthritis, psoriasis, septic shock, myocardial ischemic injury, acute respiratory distress syndrome, and multiple system organ failure. The goal of this research program is to increase our understanding of the specific and overall roles that complement anaphylatoxin peptides and their receptors play in inflammation and immunity. During the next several years, the cellular expression and biological functions mediated by the C3a receptor will be examined in detail. In addition, the in vivo biological role of the C3a receptor will be studied and evaluated using a C3a receptor """"""""knock-out"""""""" mouse in several well-characterized models of inflammation, infection, and autoimmunity. These studies will be accomplished by four major specific aims: 1) to determine the cells in peripheral blood and selected tissues that express the C3a anaphylatoxin receptor, and to delineate C3a mediated biological functions by cells expressing the C3a receptor, 2) to determine the effect of C3a receptor deficiency on pulmonary inflammation in established models of immune-complex injury, asthma, and bacterial infection and clearance, 3) to determine the effect of C3a receptor deficiency in the skin using established models of infectious dermatitis, immune-complex injury, and bullous pemphigoid, and 4) to determine the effect of C3a receptor deficiency in the peritoneum using established models of immune-complex peritonitis, acute septic peritonitis, and septic shock.
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