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  • Research Projects: Ducruet Laboratory

    Tissue-plasminogen Activator (tPA)-mediated Complement Cascade Activation

    One focus of our work has been to characterize an important pathway of complement activation that occurs in the setting of tPA administration during stroke.

    Using a murine model of reperfused stroke, we have shown that intravenous tPA promotes the generation of C3a anaphylatoxin in ischemic brain through a novel plasmin-mediated complement activation pathway that has not been previously described in stroke. Intravenous tPA exacerbates hemorrhagic conversion and cerebral edema in our stroke model, which mirrors observations in the treatment of human stroke patients.

    However, pharmacologic blockade of the C3a receptor suppresses these deleterious effects of tPA in stroke.  Using both in vitro and in vivo models, we also are working to delineate the mechanisms underlying complement-mediated vascular dysfunction in ischemic brain.

    Complement in Synapse Elimination

    We also have begun to investigate the role of complement in the remodeling of neuronal synapses that occurs following cerebral ischemia.

    Complement expression has been shown to underlie the process of pruning of synapses by microglia that occurs in normal development. We hypothesize that this process is dysregulated in ischemic brain.

    We have found complement components C1q and C3 strongly expressed in close association with both pre- and postsynaptic markers in the peri-infarct cortex, and are currently working to delineate the role that synaptic complement plays in both injury and recovery in the subacute phase of stroke.

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