Development of neuromuscular junctions in children with cerebral palsy

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DESCRIPTION (provided by applicant): The development of interventions that enhance the productivity, independence, quality of life, and health of persons with cerebral palsy (CP) is a major long-term goal for pediatric translational research. Approximately 24 in every 10,000 children aged 3-10 years have a physical disability attributable to CP. CP patients exhibit poor motor control, spasticity, weakness, ataxia, and rigidity. The PIs seek to improve the functional status of patients with CP and to simplify their medical, surgical, and therapeutic management by studying the cellular/molecular mechanisms contributing to their physical impairment. Of critical importance is a complete understanding of nerve-muscle interactions as they occur in CP. In previous research, the PIs found that children with CP have disrupted nerve-muscle interactions evidenced by disorganized neuromuscular junctions (NMJs). They further found that the degree of this NMJ disorganization was associated with the level of functional ability in children with CP. These results are unexpected; NMJ organization has been well studied and the co-localization of junctional components in mature NMJs found to be highly controlled. The results, therefore, suggest that nerve-muscle interactions in CP are fundamentally dysregulated or that NMJs in CP patients fail to mature completely. Since children with CP exhibit delayed motor development, and since there is a strong association between premature delivery and CP, the PIs suspect that the observed NMJ deformations are due to delayed or arrested junctional maturation, which is normally completed early in life. With the current application, the PIs seek data regarding the developmental status of NMJs in children with CP. By evaluating muscle biopsies collected during surgery, they will test the hypothesis that CP prolongs NMJ immaturity through childhood and into adolescence resulting in diminished neuromotor function. Immature NMJs, which are normally present prenatally and in infancy, are distinguished from mature NMJs by both structural and molecular-biochemical phenotypes. The PIs will test their hypothesis by analyzing NMJ structure (Aim 1) and the expression of proteins associated with NMJ maturation (Aim 2). Enrolled subjects will undergo functional assessment by physical therapists prior to surgery. Biopsy material collected from specified anatomic sites will be compared between a CP group of children and a control group. In this way the PIs will determine if children with CP have NMJs with an immature phenotype and whether the NMJ maturational phenotype is associated with functional ability. Cerebral palsy (CP) is one of the most common causes of severe pediatric physical disability in the industrialized world. Despite its prevalence and the profound debilitation of muscle control associated with the disease, very little is known about the specific interactions between the nervous system and the muscles of patients with CP. The PIs study these interactions in order to develop therapies and treatments that will improve and sustain the physical ability and health of patients with CP.