Grants Funded

Abstract

Impact Statement: Nerve injuries impart significant physical, psychosocial, and economic burdens on individuals and society, and less than half of patients achieve baseline motor recovery. The proposed research investigates signaling mechanisms driving terminal Schwann cell injury response and neuromuscular junction reinnervation after nerve injury and repair. Knowledge from these studies will illuminate novel therapeutic strategies to improve muscle functional outcomes for patients with nerve injury and help to alleviate the individual and societal burdens associated with these conditions.

Project Summary: Recovery of muscle function following motor nerve injury remains limited; patients often do not regain baseline function. The neuromuscular junction (NMJ), the synapse between the nerve and its target muscle, is an understudied component of peripheral nerve injury. Defects at the NMJ occur after nerve injury and have functional consequences. The NMJ includes nonmyelinating glia called terminal Schwann cells (tSCs). After nerve injury, tSCs extend cytoplasmic processes between NMJs to guide axon growth and NMJ reinnervation. Without these tSC process, NMJ reinnervation and muscle function are negatively impacted. The signaling pathways mediating tSC process extension are unknown. Increased knowledge of the NMJ events occurring in response to nerve injury and repair is required to improve clinically-relevant functional outcomes. Vascular endothelial growth factor (VEGF) signaling has been associated with nerve regeneration after injury, and recent evidence indicates the importance of this signaling at the NMJ following nerve injury. Inhibition of the VEGF cascade decreases tSC process extension, NMJ reinnervation, and muscle function. We hypothesize that VEGF interacts directly with tSCs after nerve injury to support NMJ reinnervation via tSC process extension, and this phenomenon may be enhanced indirectly via angiogenesis. This proposal focuses on the interactions of VEGF signaling with tSCs and endothelial cells (ECs) to drive NMJ reinnervation following sciatic nerve injury and immediate repair in different mouse models. We will investigate our hypothesis via the following specific aims: 1) Identify requirements for VEGF signaling on tSC process extension after acute nerve injury, 2) Identify requirements for tSC process guidance via VEGF-induced angiogenesis on NMJ reinnervation after acute nerve injury, and 3) Investigate the impact of VEGF enhancement within the target muscle on NMJ reinnervation and muscle recovery after acute and chronic nerve injury. The data from this proposal will determine the mechanisms supporting tSC injury response and NMJ reinnervation and will illuminate novel signaling pathways involved at the NMJ during motor recovery, specifically involving tSCs. Identification of the timing, importance, and function of these signaling mediators may allow translational application of treatment strategies to better protect the target muscle and improve motor recovery after peripheral nerve injury.

Biography
Dr. Alison Snyder-Warwick is an Associate Professor of Surgery in the Division of Plastic and Reconstructive Surgery and Director of the Facial Nerve Institute at Washington University in St. Louis. Dr. Snyder-Warwick completed medical school, a research fellowship in Developmental Biology, and surgical residency training all at Wash U. She then travelled to Toronto, Canada for specialized training in pediatric plastic surgery and pediatric microsurgery at the Hospital for Sick Children. Dr. Snyder-Warwick’s main clinical focus includes pediatric plastic surgery and reconstruction for facial nerve disorders, treatment of facial clefts, reconstruction of brachial plexus birth injuries, gender-affirming surgery, and pediatric and adult microsurgical procedures. Her clinical interests have led to pioneering basic science research investigations involving the terminal Schwann cell, a unique glial cell present at the nerve-muscle interface. Dr. Snyder-Warwick is passionate about helping children and adults with facial paralysis, nerve-related injuries, and facial anomalies and is committed to studying novel techniques of optimizing care for people affected by peripheral nerve pathology and facial differences.