Novel Immunotoxin and IGF Therapy for Strabismus

新型免疫毒素和 IGF 治疗斜视

• 批准号: 8338294
• 负责人: LINDA K. MCLOON
• 金额: $ 55.16万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338294
• 关键词: Adult; Aftercare; Amblyopia; Antibodies; BMP4; Blindness; Brain; Brain-Derived Neurotrophic Factor; Calibration; Child; Childhood; Data; Development; Diagnosis; Disease; Early treatment; Etiology; Excision; Eye; Eye Movements; Failure; Generations; Goals; Growth; Growth Factor; Growth Factor Receptors; Human; IGF1 gene; Immunotoxins; Individual; Infant; Injury; Insulin-Like Growth Factor I; Knowledge; Lead; Maintenance; Methods; Modeling; Molecular; Monkeys; Motor; Motor Neurons; Movement; Muscle; Nerve; Neuromuscular Junction; Neuronal Plasticity; Neurons; Operative Surgical Procedures; Oryctolagus cuniculus; Pattern; Physiological; Plastics; Positioning Attribute; Property; Sensory; Signal Transduction; Strabismus; Structure; Synapses; Synaptic plasticity; System; Testing; Translating; United States; Vision; alternative treatment; axon growth; base; critical period; density; gaze; improved; infancy; mind control; motor control; nerve supply; nonhuman primate; novel; oculomotor; orbit muscle; prevent; receptor expression; satellite cell

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.

描述（由申请人提供）：我们的研究致力于预防治疗婴儿并获得的斜视。每年在美国出生的孩子中至少有3％被诊断出患有斜视。斜视的早期治疗可以防止视觉功能的丧失，但是斜视管理仍然具有挑战性。这部分是因为我们对其病因缺乏明确的理解。我们的研究将填补这一知识的空白，并导致改善斜视的疗法。在某些情况下，眼睛错位可能是由于单个眼外肌（EOM）或特定肌肉室的强直神经支配的校准不当。获得的斜视可能会遵循EOM的伤害或其神经支配。最终，眼睛对齐，凝视和眼动的动作都取决于提供给EOM的眼运动神经支配的质量。我们的研究将确定当前的手术方法和生长因子的新应用如何改变与眼睛比对相关的动眼神经元特性。我们的长期目标是开发药物疗法，通过改变内在的神经元发射特性和神经密度和神经神经元的神经神经元上的神经神经元网络来调节EOM的“不足”或“过度作用” EOM的力，从而使EOM支配以允许突触可塑性和运动融合。我们将在感官诱导的斜视的非人类灵长类动物模型中测试这些策略。我们还希望预防正常人类斜视手术后发生的不适，以降低手术衰竭率。我们有5个具体目标：I。影响轴突生长并维持眼外肌肉的神经模式的分子信号是什么？我们将分析兔EOM中生长因子和受体表达的模式，然后使用外源添加的生长因子或抗体调节神经支配模式和密度。 ii。可以操纵EOM神经，以便预防手术衰退和/或切除后发生的肌肉水平的疾病吗？我们将通过促进或预防卫星细胞和/或神经发芽和神经肌肉结的形成来操纵EOM的神经生长。 iii。我们可以调节成熟运动神经元周围的会内神经元网，这是否导致持续生长因子处理后突触连接改变？我们将定义会内神经元的净结构，并确定持续释放BDNF，IGF1和BMP4的功效来调节会内神经元网络，并确定它是否会恢复运动神经元突触可塑性。 iv。我们经过验证的生长因子如何改变正常非人类灵长类动物的眼部运动系统中的眼动神经元发射特性？我们将分析我们开创的IGF-1和BMP4治疗后的神经元发射率，这会增加或降低力的产生或肌肉大小。 V.我们假设生长因素可以有效地治疗斜视。我们将使用我们既定的方法在婴儿猴子中产生感官诱导的斜视，然后评估采用生长因子治疗以纠正眼睛未对准的新型治疗方法。 公共卫生相关性：每年在美国出生的孩子中至少有3％被诊断出患有斜视。斜视的早期治疗可以防止视觉功能的丧失，但是斜视管理仍然具有挑战性。我们的长期目标是开发药物疗法，通过改变内在的神经元发射特性和神经密度和神经神经元的神经神经元上的神经神经元网络来调节EOM的“不足”或“过度作用” EOM的力，从而使EOM支配以允许突触可塑性和运动融合。