Novel Immunotoxin and IGF Therapy for Strabismus

描述(由申请人提供)：我们的研究针对的是先进的治疗方法，以治愈婴儿和后天性斜视。在美国出生的儿童中，每年至少有3%被诊断为斜视。斜视的早期治疗可以防止视觉功能的丧失，但斜视的管理仍然具有挑战性。这在一定程度上是因为我们对其病因缺乏明确的了解。我们的研究将填补这一知识空白，并导致斜视治疗方法的改进。在某些情况下，眼睛错位很可能是由于对个别眼外肌(EOM)或特定肌肉间隔的紧张性神经支配的不正确校准。后天性斜视可发生在EOM或其神经损伤后。归根结底，眼球对准、凝视和眼球运动都取决于提供给EOM的眼运动神经支配的质量。我们的研究将确定目前的手术方法和生长因子的新应用如何改变与眼球排列相关的动眼神经属性。我们的长期目标是开发药物疗法，通过改变固有的神经元放电特性和神经密度，并调节支配EOM的运动神经元上的神经周网络，以实现突触可塑性和运动融合，从而调节“作用不足”或“过度作用”的EOM的力量。我们将在感觉性斜视的非人类灵长类动物模型中测试这些策略。我们还希望预防人类正常斜视手术后发生的适应不良，以降低手术失败率。我们有5个具体目标：1.影响轴突生长和维持眼外肌神经支配模式的分子信号是什么？我们将分析生长因子和受体在兔EOM中的表达模式，然后使用外源性添加的生长因子或抗体来调节神经模式和密度。手术后退和/或切除后，是否可以操作EOM神经，以防止肌肉水平的不适应？我们将通过促进或阻止卫星细胞的增殖和/或神经发芽和神经肌肉接头的形成来控制EOM中的神经生长。我们能否调节成熟运动神经元周围的神经周神经网络，在持续的生长因子治疗后，这是否会导致突触连接的改变？我们将定义神经周网络结构，并确定缓释BDNF、IGF1和BMP4对神经周网络的调节效果，并确定其是否能恢复运动神经元的突触可塑性。我们已证实的生长因子如何改变正常非人类灵长类动物眼运动系统中动眼神经元的放电特性？我们将分析在我们首创的治疗方法IGF-1和BMP4之后的神经元放电率，这两种治疗方法可以增加或减少力量产生和肌肉大小。我们假设生长因子可以有效地治疗斜视。我们将使用我们已建立的方法在幼猴身上制造感觉性斜视，然后评估使用生长因子治疗来纠正眼睛错位的新疗法。 公共卫生相关性：在美国出生的儿童中，每年至少有3%被诊断为斜视。斜视的早期治疗可以防止视觉功能的丧失，但斜视的管理仍然具有挑战性。我们的长期目标是开发药物疗法，通过改变固有的神经元放电特性和神经密度，并调节支配EOM的运动神经元上的神经周网络，以实现突触可塑性和运动融合，从而调节“作用不足”或“过度作用”的EOM的力量。

DESCRIPTION (provided by applicant): Our studies are directed at advancing treatments to cure infantile and acquired strabismus. At least 3% of the children born in the U.S. are diagnosed with strabismus each year. Early treatment of strabismus can prevent loss of visual function, but strabismus management remains challenging. This is partly because we lack a definitive understanding of its etiology. Our studies will fill this gap in knowledge and lead to improved therapies for strabismus. Eye misalignment in some cases is likely due to improper calibration of the tonic innervation of individual extraocular muscles (EOM) or specific muscle compartments. Acquired strabismus may follow injury of EOM or their innervation. Ultimately, eye alignment, gaze-holding and eye movements all depend on the quality of ocular motor innervation supplied to the EOM. Our studies will determine how current surgical methods and novel application of growth factors alter oculomotor neuronal properties associated with eye alignment. Our long term goal is to develop pharmacologic therapies to modulate force in an "underacting" or "overacting" EOM by changing intrinsic neuronal firing properties and innervational density and modulating perineuronal nets on the motor neurons that innervate the EOM to allow for synaptic plasticity and motor fusion. We will test these strategies in a non-human primate model of sensory-induced strabismus. We also hope to prevent maladaptations that occur after normal human strabismus surgery in order to reduce surgical failure rate. We have 5 specific aims: I. What are the molecular signals that influence the growth of axons and maintain the innervational pattern of the extraocular muscles? We will analyze patterns of growth factor and receptor expression in rabbit EOM, followed by use of exogenously added growth factors or antibodies to modulate the innervational pattern and density. II. Can EOM innervation be manipulated so that maladaptations at the muscle level that occur after surgical recession and/or resection are prevented? We will manipulate nerve growth in EOM by either promoting or preventing proliferation of satellite cells and/or nerve sprouting and neuromuscular junction formation. III. Can we modulate the perineuronal nets around mature motor neurons, and does this result in altered synaptic connections after sustained growth factor treatments? We will define perineuronal net structure and determine efficacy of sustained release BDNF, IGF1, and BMP4 to modulate perineuronal nets, and determine if it will restore motor neuron synaptic plasticity. IV. How do our proven growth factors alter oculomotor neuronal firing properties in the ocular motor system of normal non- human primates? We will analyze neuronal firing rates after treatments we pioneered, IGF-1 and BMP4, which increase or decrease force generation and muscle size. V. We hypothesize that growth factors can effectively treat strabismus. We will use our established methods to produce sensory-induced strabismus in infant monkeys, and then evaluate novel treatments employing growth factor treatments to correct eye misalignment. PUBLIC HEALTH RELEVANCE: At least 3% of the children born in the United States are diagnosed with strabismus every year. Early treatment of strabismus can prevent loss of visual function, but strabismus management remains challenging. Our long term goal is to develop pharmacologic therapies to modulate force in an "underacting" or "overacting" EOM by changing intrinsic neuronal firing properties and innervational density and modulating perineuronal nets on the motor neurons that innervate the EOM to allow for synaptic plasticity and motor fusion.