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.

项目摘要/摘要： 神经退行性疾病中的肌萎缩性侧索硬化症（ALS）导致导致 运动神经元导致麻痹的运动神经元的逐渐恶化和功能丧失。研究 表明在神经肌肉连接处（NMJ）的合成传播早期减少 疾病的阶段NMJ神经支配发生在脊髓中的神经元细胞体时 保持完整。 NMJ功能障碍先于运动神经元死亡的观察结果 建议ALS是一种“垂死”的神经病。 ALS的病因目前尚不清楚，没有 ALS的有效治疗可改善神经肌肉传播，这将改善 ALS患者的生活质量通过增加神经肌肉强度并可能延长寿命。 因此，我的长期目标是确定一种新的干预方法来改善神经肌肉 通过减少ALS中垂死的神经病的功能。我们的策略是测试一种新颖的CAV2特异性 我们开发的电压门控钙通道门控修饰符（GV-58），A 加强神经肌肉系统激活的药理干预措施。 GV-58 具有创新性，因为它基于以前尚未对ALS进行测试的目标，即 加强突触传播以维持NMJ神经。在这里，我们建议 表征在SOD1G93A中疾病进展的不同阶段的神经肌肉无力 ALS模拟小鼠并测试GV-58的效果，无论是急性慢性给药。 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 强度以及是否可以改善SOD1G93A小鼠的存活率。