Grants We Funded

Abstract
Following peripheral nerve injury and reconstruction, a major factor contributing to the limited return of motor function is the time required for the regenerating nerve to reach its target muscle. The calcineurin binding agent FK-506 (tacrolimus) has demonstrated the ability to accelerate nerve regeneration and accelerate restoration of function following peripheral nerve injury. However, its immunosuppressive properties make it undesirable for use in neurological situations not requiring immunosuppression. FK-506 acts directly on neurons to enhances regeneration by binding to heat shock protein 90 (Hsp-90) and disrupting the steroid receptor complex. In vitro studies have shown that agents that bind Hsp-90 enhance neurite extension in neuronal cell cultures. These Hsp-90 binging agents have yet to be extensively evaluated for there ability to enhance peripheral nerve regeneration in vivo, however other analogs of FK-506 that have shown promise in vitro have demonstrated short commings in vivo. Peripheral nerve regeneration in vivo is fundamentally different than simulating regeneration in in vitro because of Wallerian degeneration (WD). WD in vivo is necessary for peripheral nerve regeneration and is partially carried out through activation of the innate immune response. Recently, it was demonstrated that increased levels of calcineurin (the target of inhibition by FK-506 in vivo) reduces the activation of the innate immune response. Delays in WD in the distal stump have been shown to negatively affect nerve regeneration. It is likely that FK-506 not only stimulates nerve regeneration by acting on the neuron, but also prepares the distal stump for that regeneration by enhancing the innate immune response and thus WD through suppression of calcineurin. Here we propose to investigate the contributions of both these FK-506 derived mechanism of nerve regeneration by evaluating each mechanism independently in comparison to treatment with FK-506.

Biography
Philip Johnson received his Ph.D. in Biomedical Engineering from Washington University in St. Louis. His research expertise is in cell transplant therapies, drug delivery techniques, tissue engineering, and evaluation of implantable biomaterials (in vivo/ in vitro). Current research interests include utilizing neural tissue engineering techniques to enhance peripheral nerve regeneration. Specifically, he is interested in the mechanism of FK-506 mediated enhancement of nerve regeneration through direct action on regenerating neurons and through stimulation of the innate wound healing response. His lab is also interested in the augmentation of decellularized tissues through chemical conjugation to enhance their roles as mediums for cell transplantation and scaffolds for tissue synthesis. His research has been recognized for excellence by the Society for Biomaterials. He is currently the director of the Peripheral Nerve Research Laboratory at Washington University School of Medicine.