TROPHIC MANIPULATIONS OF THE OCULOMOTOR SYSTEM

描述（改编自申请人摘要）：斜视是一种未对准 这可能导致严重的缺陷，如失去视觉轴， 中央视力从一只眼睛，称为弱视。斜视相对来说 在一般人群中很常见，估计为5 - 6%。的病因 斜视是多因素的。目前的视力恢复疗法 对准包括通过手术后退或药物治疗 肉毒杆菌毒素去神经和手术切除肌肉紧缩。 在拟议的研究项目中，眼肌和 将探索支配眼神经元的长期目标， 药物治疗对斜视手术治疗补充 针对营养相互作用。营养因子或营养素的注射 拮抗剂进入选定的眼肌可以恢复平衡的眼球运动， 模仿内在营养机制。拟议的研究将在一个 眼神经元和眼肌的营养操作的动物模型 可以调整这些肌肉的力量，增加眼球的存活率 神经元在发育过程中，侧支轴突分支的数量增加， 眼神经元，并维持轴突侧支和终板。研究将 确定哪些营养因子在眼肌中产生， 它们对肌肉质量，肌肉力量，神经发芽， 轴突或终板的维持。进一步的研究将确定是否 肌源性因子逆行输送到眼内 并支持这些神经元的存活。营养的时间进程 眼部肌肉和神经之间的相互作用将与 目的是了解和操纵营养反应， 或在慢性麻痹的肌肉中，如 鸡的遗传突变体，弯颈侏儒（cn/cn）。这些研究将侧重于 四种营养因子，脑源性神经营养因子（BDNF），胶质细胞 细胞系源性神经营养因子（GDNF）和胰岛素样生长 因子（IGF I，II），以及在重新提交中添加的心肌营养素-1（CT-1）。 将筛选其他营养因子，以确定其修饰细胞的潜力。 眼部肌肉的力量。一种结合了药理学分子学生理学 包括超微结构水平的形态学方法将提供一个 对营养药物治疗的前景进行有意义的评估 斜视和其他眼肌疾病作为补充， 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.