Development of neuromuscular junctions in children with cerebral palsy

描述(由申请人提供)：提高脑瘫患者的生产力、独立性、生活质量和健康的干预措施的发展是儿科翻译研究的一个主要长期目标。每10,000名3-10岁儿童中约有24人患有可归因于CP的身体残疾。CP患者表现出运动控制不良、痉挛、虚弱、共济失调和僵硬。PI通过研究导致患者身体损害的细胞/分子机制，寻求改善CP患者的功能状态，并简化他们的内科、外科和治疗管理。最重要的是完全了解发生在脑瘫中的神经-肌肉相互作用。在之前的研究中，PI发现患有CP的儿童扰乱了神经-肌肉相互作用，表现为神经肌肉连接紊乱(NMJ)。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。这些结果是意想不到的；NMJ的组织已经被很好地研究了，并且发现在成熟的NMJ中连接成分的共定位是高度受控的。因此，这些结果表明，CP患者的神经-肌肉相互作用从根本上是失调的，或者是CP患者的NMJ未能完全成熟。由于患有脑性瘫痪的儿童表现出运动发育迟缓，而且早产与脑性瘫痪之间有很强的相关性，PI怀疑观察到的NMJ畸形是由于通常在生命早期完成的关节成熟延迟或停滞所致。在当前的应用中，PI寻求关于患有CP的儿童NMJ的发育状况的数据。通过评估手术期间收集的肌肉活组织检查，他们将检验这一假设，即CP会延长NMJ的不成熟时间，直到儿童和青春期，导致神经运动功能减弱。未成熟的NMJ通常存在于胎儿期和婴儿期，在结构和分子生化表型上都有别于成熟的NMJ。PI将通过分析NMJ结构(目标1)和与NMJ成熟相关的蛋白质表达(目标2)来验证他们的假设。登记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将确定患有CP的儿童是否具有不成熟表型的NMJ，以及NMJ成熟表型是否与功能能力相关。 在工业化国家，脑性瘫痪是导致儿童严重肢体残疾的最常见原因之一。尽管它的流行和肌肉控制与疾病相关的严重衰弱，但对CP患者神经系统和肌肉之间的具体相互作用知之甚少。PIs研究这些相互作用，以开发将改善和维持CP患者的体能和健康的治疗方法和治疗方法。

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.