Development of neuromuscular junctions in children with cerebral palsy

描述（由申请人提供）：开发提高脑瘫（CP）患者的生产力、独立性、生活质量和健康的干预措施是儿科转化研究的一个主要长期目标。大约每10000名3-10岁儿童中就有24人因CP而身体残疾。CP患者表现为运动控制不良、痉挛、虚弱、共济失调和僵硬。PIs旨在通过研究导致CP身体损伤的细胞/分子机制，改善CP患者的功能状态，简化其医疗、手术和治疗管理。至关重要的是对CP中神经-肌肉相互作用的完整理解。在先前的研究中，pi发现CP患儿的神经-肌肉相互作用被破坏，神经肌肉连接紊乱（NMJs）就是证据。他们进一步发现，这种NMJ紊乱的程度与CP儿童的功能能力水平有关。人们对NMJ的组织进行了很好的研究，发现成熟NMJ中连接成分的共定位受到高度控制。因此，结果表明CP患者的神经-肌肉相互作用从根本上是失调的，或者CP患者的NMJs不能完全成熟。由于患有脑瘫的儿童表现出运动发育迟缓，而且早产与脑瘫之间存在很强的联系，因此pi怀疑观察到的NMJ变形是由于关节成熟延迟或停止所致，而关节成熟通常在生命早期完成。在目前的应用中，pi寻求有关CP儿童NMJ发育状态的数据。通过评估手术中收集的肌肉活检，他们将验证CP延长NMJ不成熟的假设，从童年到青春期，导致神经运动功能减弱。未成熟的NMJs通常存在于产前和婴儿期，通过结构和分子生化表型将其与成熟的NMJs区分开来。pi将通过分析NMJ结构（目的1）和与NMJ成熟相关的蛋白质表达（目的2）来验证他们的假设。入组的受试者将在手术前接受物理治疗师的功能评估。从特定解剖部位收集的活检材料将在CP组儿童和对照组之间进行比较。通过这种方式，pi将确定CP患儿是否具有未成熟表型的NMJ，以及NMJ成熟表型是否与功能能力相关。

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.