TROPHIC MANIPULATIONS OF THE OCULOMOTOR SYSTEM

描述（由申请人提供）：斜视是一种视轴错位，在一般人群中相对常见，估计为5-6%。当这种疾病发生在婴儿身上时，它会导致严重的缺陷，比如一只眼睛的中心视力丧失，即弱视。目前恢复视力的治疗方法是通过手术切除或肉毒杆菌毒素药物去神经支配和手术切除肌肉收紧来削弱相对太强的对抗性眼肌。目前还没有一种治疗方法可以增强较弱的肌肉。提出的研究是基于最近的证据表明，肌肉的力量是由营养因子调节的。实验旨在确定直接影响肌纤维或在眼肌和支配运动神经元之间提供反馈信号的营养因子。从长远来看，该项目旨在通过针对营养相互作用的药物治疗来补充斜视的手术治疗。利用一种有利的鸡动物模型，我们将验证在实验中被削弱的发育中的眼肌可以通过营养因子得到增强的假设。在发育的关键时期，将营养因子注射到选定的眼肌中，可以通过模仿内在营养机制来恢复平衡的眼球运动。将探讨急性和慢性应用营养因子的有效性和持续时间。进一步的研究将描述由肉毒杆菌毒素、机械性去神经支配或肌肉损伤引起的适应性反应（分子、生理和形态学）。将分析运动神经元变性突变小鼠模型中营养因子的转运，以确定运动神经元变性的潜在原因。将对不同年龄的弱视肌和强视肌进行检查，比较营养因子及其受体的表达。我们的研究将集中于在眼球运动系统中具有既定作用的营养因子：胶质细胞系衍生的神经营养因子（GDNF），胰岛素样生长因子（igf）和心肌营养因子-1 （CT-1）。结合药理学、分子、生理学和形态学方法，包括超结构水平，将为斜视和其他眼肌疾病的营养、药理学治疗前景提供有意义的评估，作为当前手术和去神经支配手术的替代或补充。

DESCRIPTION (provided by applicant): Strabismus is a misalignment of the visual axes which is relatively common in the general population with estimates of 5-6%. When this disorder occurs in infants, it can lead to severe deficiencies such as loss of central vision from one eye, known as amblyopia. Current therapies for restoration of visual alignment are based on weakening the relatively too strong antagonistic eye muscle, either by surgical recession or pharmacological denervation with botulinum toxin and muscle tightening by surgical resection. There is currently no therapeutic approach that strengthens the weaker muscle. The proposed research is based on recent evidence showing that the strength of muscles is regulated by trophic factors. Experiments were designed to identify trophic factors that either directly affect muscle fibers or provide feedback signals between eye muscles and innervating motor neurons. In the long-term, this project seeks to supplement surgical treatment of strabismus with a pharmacological treatment targeted at trophic interactions. Using an advantageous chicken animal model, we will test the hypothesis that an experimentally weakened developing eye muscle can be strengthened with trophic factors. Injections of trophic factors into selected eye muscles during a critical period of development may restore balanced eye movements by mimicking intrinsic trophic mechanisms. The effectiveness and duration of acute and chronic application of trophic factors will be explored. Additional studies will characterize adaptive responses (molecular, physiological and morphological) that are induced by denervation with botulinum toxin, mechanical denervation, or muscle lesion. Trafficking of trophic factors in mutant mouse models with motor neuron degeneration will be analyzed to identify underlying causes of motor degeneration. Weak and strong human eye muscles of different ages will be examined to compare expression of trophic factors and their receptors. Our studies will focus on trophic factors with established effects in the oculomotor system: glial cell line-derived neurotrophic factor (GDNF), insulin-like growth factors (IGFs), and cardiotrophin-1 (CT-1). A combined pharmacological, molecular, physiological and morphological approach, including the ultra-structural level, will provide a meaningful assessment of the prospects for a trophic, pharmacological treatment of strabismus and other eye muscle disorders as an alternative or supplement to current surgical and denervation procedures.