C-reactive protein (CRP) as a pathological factor in inflammation and ischemia/reperfusion injury: therapeutic implications

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C-reactive protein (CRP) is a highly conserved pentameric protein and is the prototypic acute phase protein. Recently it has been identified not only as a marker, but also causal factor of the inflammatory response. We could previously show in vitro and in vivo that in inflamed tissue local cell damage and membrane changes lead to dissociation of the circulating pentameric CRP (pCRP) into its monomeric subunits (monomeric=mCRP). The resulting mCRP is deposited in the area of inflammation and leads to a localized aggravation of the existing inflammatory response. The identification of CRP as locally activated pro-inflammatory system lead to the development of novel anti-inflammatory therapeutic strategies by us. These are targeting the dissociation process from pCRP to mCRP by stabilizing CRP with 1,6-bis-(Phosphocholin)-hexan, a chemically modified derivative of the CRP ligand phosphocholin. In our previous in vivo proof-of-concept study we could demonstrate the anti-inflammatory potential of this therapeutic concept. In this project we will now analyse the molecular mechanisms by which mCRP modulates inflammation. With site directed mutagenesis of CRP we will identify the pro-inflammatory sequences within the CRP primary structure and the role of relevant binding sites for described interaction partners of CRP in inflammation. This will allow for a better understanding of the underlying molecular mechanisms that in turn will allow for the identification of novel therapeutic approaches, as well as improving our existing therapeutic agents. After the identification of a novel pathological pro-inflammatory mechanism in our previous work and the proof-of-concept of the effectiveness of therapeutically targeting CRP we will now continue our work by developing and improving novel CRP-blocking agents based on the exact identification of the involved molecular mechanisms. These novel agents will then be screened and tested in in vitro and in vivo in animal models of inflammatory diseases and will ultimately represent a novel class of anti-inflammatory agents to be transferred into the clinical setting.