Human C-Reactive Protein (CRP) is the prototype of a number of proteins which share the property of increasing their plasma concentration following injury and which are collectively referred to as """"""""acute-phase proteins"""""""". The objective of the proposed research is to define the biologic role of CRP. Our working hypothesis is that the function of CRP relates to its ability to specifically recognize foreign pathogens and damaged or necrotic cells of the host and to initiate their elimination by interacting with the complement system and with phagocytic cells. We propose to approach our objectives by pursuing the following specific aims: 1) Define the structural determinants of the phosphocholine-binding site of CRP. In a first stage we will construct recombinant SV40-CRP viruses and utilize them to express the protein in mammalian cells. In a second stage we will map the topology and chemical nature of the binding site by using site-directed mutagenesis. 2) Define the structural determinants of the effector functions of CRP. Both the C1q binding/complement activating site and the site reacting with the CRP receptor on human neutrophils will be characterized. Initial definition of the sites will utilize monoclonal antibodies and more detailed characterization site-directed mutagenesis. 3) Further study the in-vivo protective effects of CRP against bacterial infections in the murine model. We are particularly interested in defining in-vivo synergistic effects between CRP and antibodies, as well as between CRP and complement opsonins. These combined studies will lead to an increased understanding of host- defense mechanisms.
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