TROPHIC MANIPULATIONS OF THE OCULOMOTOR SYSTEM

描述(摘自申请者的摘要)：斜视是一种错位 可导致严重的缺陷，如视轴丢失 一只眼睛的中央视觉，称为弱视。斜视是相对的 在普通人群中很常见，估计为5%-6%。该病的病因学 斜视是多因素的。目前视力恢复的治疗方法 对齐包括通过外科手术或药物治疗使肌肉变弱。 肉毒杆菌毒素去神经和手术切除肌肉紧缩术。 在拟议的研究项目中，眼肌和眼肌之间的营养调节 将探索神经支配动眼神经元，长期目标是 斜视手术治疗的辅助药物治疗 以营养相互作用为目标。注射营养因子或营养因子 进入选定眼肌的拮抗剂可以通过以下方式恢复平衡的眼球运动 模仿内在的营养机制。拟议的研究将在一个 动眼神经和眼肌营养操作的动物模型 可以调节这些肌肉的力量，增加动眼神经的存活率 神经元在发育过程中，增加侧枝轴突的数量 动眼神经，并维持轴突侧支和终板。研究将会 确定哪些营养因子是在眼肌中产生的， 它们对肌肉质量、肌肉力量、神经萌发和 轴突或终板的维护。更多的研究将确定 肌源性因子被逆行输送到动眼神经。 并支持这些神经元的生存。营养化的时间进程 眼部肌肉和它们的神经之间的相互作用将通过 目的了解和操控由以下因素引起的营养反应 用肉毒杆菌毒素去神经或慢性瘫痪的肌肉，如 禽类遗传突变体，弯颈矮小症(CN/CN)。这些研究将集中在 四种营养因子，脑源性神经营养因子，胶质细胞 细胞源性神经营养因子与胰岛素样生长 因子(IGF I、II)，以及在重新提交中添加的心肌营养素-1(CT-1)。 将筛选额外的营养因子，以确定它们是否有可能改变 眼肌的力量。一种药理、分子、生理相结合的 包括超微结构水平在内的形态方法将提供 对营养性药物治疗前景的有意义的评估 斜视和其他眼肌疾病作为当前的补充 切除和去神经手术。

DESCRIPTION (Adapted from applicant's abstract): Strabismus is a misalignment of the visual axis, which can lead to severe deficiencies such as loss of central vision from one eye, known as amblyopia. Strabismus is relatively common in the general population with estimates of 5-6 percent. The etiology of strabismus is multifactorial. Current therapies for restoration of visual alignment include muscle weakening by surgical recession or pharmacological denervation with botulinum toxin and muscle tightening by surgical resection. In the proposed research project, the trophic regulation between eye muscles an innervating oculomotor neurons will be explored with the long-term goal to supplement surgical treatment of strabismus with a pharmacological treatment targeted at trophic interactions. Injections of trophic factors or trophic antagonists into selected eye muscles may restore balanced eye movements by mimicking intrinsic trophic mechanisms. The proposed studies will test in an animal model how trophic manipulations of oculomotor neurons and eye muscles can adjust the strength of these muscles, increase the survival of oculomotor neurons during development, increase numbers of collateral axonal branches of oculomotor neurons, and maintain axon collaterals and endplates. Studies will determine which trophic factors are produced in the eye muscles, which functions they have on muscle mass, muscle strength, nerve sprouting, and maintenance of axons or endplates. Additional studies will determine whether the muscle-derived factors are transported retrogradely to the oculomotor neurons and support the survival of these neurons. The time course of trophic interactions between eye muscles and their nerves will be explored with the goal to understand and manipulate the trophic responses which are induced by denervation with botulinum toxin or in chronically paralyzed muscle such as the avian genetic mutant, crooked neck dwarf (cn/cn). These studies will focus on four trophic factors, brain-derived neurotrophic factor (BDNF), glial cell-line-derived neurotrophic factor (GDNF), and the insulin-like growth factors (IGF I, II), and, added in the resubmission, cardiotrophin-1 (CT-1). Additional trophic factors will be screened for their potential to modify the strength of eye muscles. A combined pharmacological, molecular, physiological and morphological approach including the ultrastructural level will provide a meaningful assessment of the prospects for a trophic, pharmacological treatment of strabismus and other eye muscle disorders as a supplement to current resection and denervation procedures.