CRP-based Targeting and Signaling
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Revision as of 01:23, 27 October 2007
1) MI induces large increase in serum CRP levels
2) CRP deposits onto damaged myocardial cells (it binds to small nuclear ribonucleoproteins)
3) Our cells expressing FcGammaRIIa-R131 bind CRP on the surface of damaged cells and in the serum surrounding the damaged area.
4) Crosslinking of the receptors induces the phosphorylation of the ITAMs in the intracellular region of the receptor.
5) Syk is recruited to the receptor and becomes phosphorylated at ITAMs.
6) Crosslinking of the receptors also recruits p85 which binds to the phosphorylated Tyr-317 residue on Syk.
7) This interchange allows for the inteins (dnaEc-VP16AD at C terminus of Syk and dnaEn-mLexA at N terminus of p85) to interact and self-splice.
8) Self splicing of the inteins produces the VP16AD-mLexA needed for downstream signaling.
Benefits: Binds to CRP on damaged cells to allow for targeting of therapeutic agents (versatile since CRP is expressed in a variety of inflammed tissues). Our system also removes CRP from the region surrounding the damaged area, lessening the damage caused by CRP and increasing the chance of full recovery.
Problems: FcGamma can bind IgG present in serum. Although the FcGammaRIIa-R131 exhibits weak affinity for IgG the possibility of binding and crosslinking the receptor is still there. This problem can be alleviated if the the FcGamma-CRP system is used as part of an AND gate with another receptor system.
