In humans, CRP is the most characteristic acute-phase protein, since its concentration in the blood rises by as much as 1000-fold within hours from infection or tissue injury. 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 objective by pursuing the following specific aims: l) Define the structural correlates of CRP function. The topology and chemical nature of the phosphocholine, fibronectin, Clq, C4, and, neutrophil receptor binding sites will be described by using site- directed mutagenesis as well as protein chemistry and monoclonal antibodies. Parallel collaborative crystallographic studies will aim at producing a solution for the three-dimensional structure of the molecule. 2) Investigate the in-vivo protective effects of CRP against bacterial infections by using human CRP transgenic mice. The range of bacterial species over which CRP-dependent protection extends will be investigated by using a variety of gram-positive and gram-negative bacteria. The mechanisms of protection will be studied by determining sites and rates of bacterial clearance. In addition, the molecular basis for the CRP- dependent protection against pneumococcal infections will be investigated by passive administration of recombinant CRP mutants defective in individual CRP functions. These combined studies will lead to an increased understanding of host- defense mechanisms against bacterial pathogens and other injurious stimuli.
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