TROPHIC MANIPULATIONS OF THE OCULOMOTOR SYSTEM

描述(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，可能会导致严重的缺陷，如一只眼睛失去中心视力，称为弱视。目前恢复视线的治疗方法是通过手术后退或用肉毒杆菌毒素药物去神经以及通过手术切除收紧肌肉来削弱相对较强的对抗性眼肌。目前还没有一种治疗方法可以增强较弱的肌肉。这项拟议的研究是基于最近的证据，表明肌肉的力量受到营养因素的调节。实验旨在确定直接影响肌肉纤维或在眼肌和神经运动神经元之间提供反馈信号的营养因子。从长远来看，该项目寻求用一种针对营养相互作用的药物治疗来补充斜视的手术治疗。使用一个有利的鸡动物模型，我们将检验这样一个假设，即经过实验削弱的发育中的眼肌可以通过营养因子得到加强。在发育的关键时期将营养因子注射到选定的眼肌中，可能会通过模仿内在的营养机制来恢复平衡的眼球运动。将探索营养因子的急性和慢性应用的有效性和持续时间。其他研究将描述由肉毒杆菌毒素去神经、机械去神经或肌肉损伤引起的适应性反应(分子、生理和形态)。将分析营养因子在运动神经元变性突变小鼠模型中的运输，以确定运动神经元变性的潜在原因。不同年龄的弱小和强壮的人类眼肌将被检查，以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：胶质细胞系源性神经营养因子(GDNF)、胰岛素样生长因子(IGFS)和心肌营养素-1(CT-1)。结合药理学、分子、生理学和形态学的方法，包括超微结构水平，将提供一个有意义的前景评估的营养，药物治疗斜视和其他眼肌疾病作为替代或补充目前的手术和去神经程序。

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.