Grants We Funded

Abstract
Creating an off-the-shelf nerve graft that can be utilized in a variety of clinical scenarios (short and long gap, small and large diameter nerves) has been a longstanding goal in nerve regeneration research. Acellular nerve allografts (ANAs) are a promising tool for nerve repair because they retain native nerve tissue extracellular matrix and structure. These components enhance axonal regeneration and are a key advantage compared to nerve conduits. However, studies with ANAs shows that they have only limited capacity for regeneration in long gap injury models (>30mm). Recent work has shown that Schwann cell (SC) senescence may play a key role in limiting nerve regeneration in long ANAs. Senescence is the state of irreversible arrest of cellular proliferation accompanied by altered gene expression and protein secretion. In long ANAs, both ischemia and cellular repopulation of a large volume may be sufficient stressors to cause senescence. The alteration in protein secretion and lack of proliferation by these senescent SCs is such that they no longer support robust nerve regeneration. Our goal is to examine two methods by which to address the problems of 1) ischemia and 2) SC repopulation of a long graft: use of vascular endothelial growth factor (VEGF) to promote angiogenesis within the avascular graft and the use of exogenous SCs. In Specific Aim 1, we will assess the effect of VEGF and exogenous SCs on nerve regeneration in long ANAs. Specific Aim 2 will examine the effect of these treatments on SC survival and senescence. These Aims will be studied using a small animal model and tissues will be analyzed via histomorphometry, immunohistochemistry, RT-PCR, and fluorescence imaging. We hypothesize that accelerating vascular growth in the graft will reduce the ischemic insult and better support SC migration and re-population of the graft. Exogenous SCs will further reduce the proliferative burden and, in concert with VEGF, reduce SC stress from ischemia. Given the interplay of vascularity and SC proliferation, the combination of these treatments may have a synergistic effect which leads to increased nerve regeneration. This study aims to create a more robust ANA that can expand the clinical utility of this off-the-shelf nerve graft so that is can be used in long gap nerve injuries. These studies will also further our understanding of factors influencing nerve regeneration and can be applied in future tissue engineering strategies.

Biography
Amy Moore, MD is currently a plastic surgery resident at Washington University in St. Louis. She obtained her medical degree at Virginia Commonwealth University School of Medicine. Dr. Moore recently completed two dedicated research years in Dr. Susan Mackinnon’s Peripheral Nerve Research Laboratory where she focused on characterizing transgenic rats that express GFP in their peripheral nerves. She recently won the Snyder Award for best resident paper at the 2009 Plastic Surgery Research Council . She also studied the enhancement of peripheral nerve regeneration through conduits with the addition of growth factors. Upon the completion of her training, Dr. Moore hopes to enter a career in academic medicine.