Biomarker of Neuroprotectant Efficacy in ALS

描述(由申请人提供)：这项第一阶段可行性研究的目标是开发一种可靠的生物标记物，用于在肌萎缩侧索硬化症(ALS)验证的小鼠模型中检测神经元损伤。目前，还没有被广泛接受的生物标志物来量化ALS诱导的运动神经元损伤。此前，我们已经证明，啮齿动物和人类的神经元退化会导致细胞骨架蛋白MAP-tau的裂解。我们的实验室已经开发出一种灵敏的酶联免疫吸附试验，可以在创伤性脑损伤和细菌性脑膜炎的啮齿动物模型中特异性地测定裂解的MAP-tau(C-tau)。 利用这种C-tau酶联免疫吸附试验，我们的初步研究表明，晚期有症状的ALS(G93A-SOD1突变)小鼠的脊髓C-tau水平是对照小鼠的10倍。Hensley等人使用旋转臂马达性能测试。最近证明，给ALS小鼠服用去甲二氢愈创木酸(NDGA)可以延缓神经功能障碍的发生。我们假设1)C-tau是ALS小鼠运动神经元损伤的可靠生物标志物，2)C-tau可以作为筛选工具来鉴定治疗ALS的神经保护药物。我们将通过确定C-tau水平与ALS小鼠神经功能缺陷进展之间的关系来检验这些假说。此外，我们将测试NDGA延缓ALS小鼠神经功能障碍发生的神经保护作用是否也对C-tau水平产生预期的影响。我们的 具体目标是： 具体目的1：比较120天ALS小鼠和对照组小鼠脊髓C-tau的水平。具体目标2：确定与对照组相比，肌萎缩侧索硬化症小鼠的C-tau水平与神经功能缺陷的关系。将在ALS和年龄匹配的对照组小鼠中测定神经功能缺陷和脊髓C-tau水平，并对疾病进展的症状前阶段和症状晚期进行统计比较。具体目标3：确定C-tau水平是否可靠地量化了ALS小鼠中已证实的神经保护剂阻力干预的效果。C-tau水平和转杆性能将作为NDGA治疗的函数进行测定和比较。

DESCRIPTION (provided by applicant): The objective of this Phase I feasibility study is to develop a reliable biomarker of neuronal damage in a validated mouse model of amyotrophic lateral sclerosis (ALS). Currently, there is no widely accepted biomarker to quantify ALS-induced motor neuron injury. Previously, we have shown that neuronal degeneration in rodents and humans results in cleavage of the cytoskeletal protein MAP-tau. Our laboratory has developed a sensitive ELISA that specifically measures cleaved MAP-tau (C-tau) in rodent models of traumatic brain injury and bacterial meningitis. Using this C-tau ELISA assay, our preliminary studies demonstrate that spinal cord C-tau levels are tenfold higher in late stage symptomatic ALS (G93A-SOD1 mutation) mice as compared to control mice. Using a rotorod motor performance assay, Hensley et al. have recently demonstrated that administration of Nor-dihydroguaiaretic acid (NDGA) to ALS mice delays onset of neurologic deficits. We hypothesize that 1) C-tau is a reliable biomarker of motor neuron injury in ALS mice and 2) C-tau can serve as a screening tool to identify neuroprotectant drags for treating ALS. We will test these hypotheses by determining the relationship between C-tau levels and progression of neurologic deficits in ALS mice. Furthermore, we will test whether the demonstrated neuroprotectant effect of NDGA that delays onset of neurologic deficits in ALS mice also exerts expected effects on C-tau levels. Our Specific Aims are: Specific Aim 1: Compare spinal cord C-tau levels in ALS mice and control mice at 120 days. Specific Aim 2: Determine the relationship between C-tau levels and neurologic deficits in ALS mice as compared to controls. Neurologic deficits and spinal cord C-tau levels will be determined in ALS and age-matched control mice and statistically compared from the presymptomatic stages to late symptomatic stages of disease progression. Specific Aim 3: Determine if C-tau levels reliably quantify the effect of a demonstrated neuroprotectant drag intervention in ALS mice. C-tau levels and rotorod performance will be determined and compared as a function of NDGA treatment.