Presynaptic degeneration in ALS mouse neuromuscular junctions and a targeted therapeutic approach

ALS 小鼠神经肌肉接头的突触前变性和靶向治疗方法

• 批准号: 10575500
• 负责人: Yomna Badawi
• 金额: $ 15.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10575500
• 关键词: ALS patients; Action Potentials; Acute; Amyotrophic Lateral Sclerosis; Back; Behavioral; Biological Assay; Calcium; Calcium Channel; Cessation of life; Chronic; Data; Defect; Denervation; Deterioration; Development; Disease; Disease Progression; Electrophysiology (science); Etiology; Exercise; Exposure to; Functional disorder; Gait; Goals; Impairment; Intervention; Investigation; Lead; Locomotion; Longevity; Measures; Methods; Motor Neurons; Motor Skills; Mus; Muscle; Muscle Weakness; Neurodegenerative Disorders; Neuromuscular Diseases; Neuromuscular Junction; Neuromuscular Junction Diseases; Neuromuscular conditions; Neuropathy; Neurotransmitters; Onset of illness; Paralysed; Peripheral nerve injury; Pharmacology; Play; Quality of life; Recovery; Rodent Model; Role; Spinal Cord; Stains; Symptoms; Synapses; Synaptic Transmission; Testing; Therapeutic Intervention; amyotrophic lateral sclerosis therapy; analog; base; behavior measurement; disabling symptom; effective therapy; exercise intervention; experimental study; improved; innovation; loss of function; motor neuron function; mouse model; muscle strength; nerve supply; nervous system disorder; neuromuscular; neuromuscular function; neuromuscular system; neuromuscular transmission; neuron loss; neuronal cell body; novel; presynaptic; prevent; release of sequestered calcium ion into cytoplasm; small molecule; superoxide dismutase 1; targeted treatment; voltage

Project Summary/Abstract: Amyotrophic Lateral Sclerosis (ALS) in a neurodegenerative disease that results in the progressive deterioration and loss of function of the motor neurons leading to paralysis. Studies indicated that synaptic transmission at neuromuscular junctions (NMJs) is reduced in early stages of the disease NMJ denervation occurs while neuronal cell bodies in the spinal cord remain intact. This observation in which NMJ dysfunction precedes motor neuron death suggests ALS is a “dying-back” neuropathy. The etiology of ALS is currently unknown, and no effective treatment exists for ALS to improve neuromuscular transmission, which would improve quality of life for ALS patients by increasing neuromuscular strength and may prolong lifespan. Therefore, my long-term goal is to identify a new intervention method to improve neuromuscular function by reducing dying-back neuropathy in ALS. Our strategy is to test a novel Cav2-specific voltage-gated calcium channel gating modifier that we have developed (GV-58), a pharmacological intervention that enhances the activation of the neuromuscular system. GV-58 is innovative because it is based on a target that has not been tested previously for ALS, namely, strengthening synaptic transmission to maintain NMJ innervation. Here, we propose to characterize neuromuscular weakness at different stages of disease progression in SOD1G93A ALS model mice and test the effects of GV-58 both acutely and after daily chronic administration. This is to determine if GV-58 can play a role in delaying disease onset or in recovery of NMJ strength and whether that can lead to improved SOD1G93A mouse survival.

项目概要/摘要： 肌萎缩侧索硬化症（ALS）是一种神经退行性疾病， 运动神经元功能的逐渐退化和丧失导致瘫痪。研究 表明神经肌肉接头（NMJ）的突触传递在早期减少， 当脊髓中的神经元细胞体 保持完整NMJ功能障碍先于运动神经元死亡的观察结果 表明ALS是一种“垂死的”神经病。ALS的病因目前尚不清楚， ALS存在有效的治疗以改善神经肌肉传递，这将改善 通过增加神经肌肉力量来改善ALS患者的生活质量，并可能延长寿命。 因此，我的长期目标是找到一种新的干预方法来改善神经肌肉 通过减少ALS中的退行性神经病变发挥作用。我们的策略是测试一种新的Cav 2特异性 电压门控钙通道门控修饰剂，我们已经开发（GV-58）， 增强神经肌肉系统激活的药物干预。GV-58 是创新的，因为它是基于一个目标，没有测试过以前的ALS，即， 加强突触传递，维持NMJ神经支配。在此，我们建议 在SOD 1G 93 A疾病进展的不同阶段表征神经肌肉无力 ALS模型小鼠，并测试GV-58急性和每日慢性给药后的作用。 这是为了确定GV-58是否可以在延迟疾病发作或恢复NMJ中发挥作用。 强度以及是否可以导致SOD 1G 93 A小鼠存活率的提高。