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

基本信息

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
项目类别：
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

项目摘要

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：肌萎缩侧索硬化症 (ALS) 是一种神经退行性疾病，会导致运动神经元功能进行性恶化和丧失，导致瘫痪。表明神经肌肉接头（NMJ）的突触传递在早期减少疾病的各个阶段 NMJ 去神经发生在脊髓中的神经元细胞体这一观察结果保持不变，其中 NMJ 功能障碍先于运动神经元死亡。表明 ALS 是一种“濒临死亡”的神经病。目前 ALS 的病因尚不清楚，也没有任何证据。 ALS 存在改善神经肌肉传递的有效治疗方法，这将改善通过增加神经肌肉力量来提高 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我们的策略是测试一种新型的 Cav2 特异性。我们开发的电压门控钙通道门控修饰剂（GV-58）增强神经肌肉系统激活的药物干预。之所以具有创新性，是因为它基于之前尚未针对 ALS 进行过测试的目标，即在这里，我们建议加强突触传递以维持 NMJ 神经支配。表征 SOD1G93A 疾病进展不同阶段的神经肌肉无力 ALS 模型小鼠并测试 GV-58 急性和每日慢性给药后的效果。这是为了确定 GV-58 是否可以发挥延迟疾病发作或 NMJ 恢复的作用强度以及是否可以提高 SOD1G93A 小鼠的存活率。