DE PEDIATRIC COBRE: PERIPHERAL NERVOUS SYSTEM IN CEREBRAL PALSY

Alfred I. Du Pont Hosp For Children, Wilmington DE

Investigators

Linked publications & trials

Abstract

This project addresses motor dysfunction in cerebral palsy (CP) by directly examining the neuromuscular junctions (NMJs) of patients with CP and by evaluating experimental systems for their ability to mimic aspects of the neuromuscular abnormalities seen in CP. CP is the most common cause of severe pediatric physical disabilities in developed countries. It originates from a non-progressive central nervous system (CNS) injury occurring early in life that leads to profound peripheral motor-system dysfunction later in life. It is our long-term goal to understand the mechanisms leading to motor-system dysfunction in CP. So far we have found that two critical components of NMJs, which are normally tightly organized, are actually disorganized in CP and that the extent of disorganization is associated with the severity of the CP. in this proposal we extend our observations to include more NMJ components, and we begin to address the development of motor system dysfunction in CP by evaluating experimental models. We have two specific aims: 1) Characterize the abnormalities of NMJs in children with CP, and 2) Develop model systems to study the pathophysiology of the peripheral nervous system in CP. In the first aim we fully characterize the organization of NMJs in CP using fluorescence microscopy to localize NMJ components, and we begin to address the physiological/clinical implications of NMJ disorganization by assessing the effects of pharmacologic agents on biopsy material. In the second aim, we evaluate two types of model system that resemble CPo These include animals that spontaneously develop conditions resembling CP due to mutations and animals that develop a CNS deficit known as pedventricutar leukomalacia, which is strongly associated with CP in low birth weight infants. Evaluating the formation of disorganized NMJs in these systems will help us identify potential mechanisms involved in the cascade from CNS injury to motor system failure and will hopefully lead us to experimental models for studying the development of abnormal NMJs.