Biomarker of Neurotoxicity in Meningitis

描述(由申请人提供)：本第一阶段申请的目的 是开发一种敏感的生物标记物来量化神经毒性和 脑膜炎的神经保护剂疗效。以前的研究文献表明，大脑 脑膜炎引起的损伤影响到多个脑区，具有异质性 分发。我们之前已经证明了细胞骨架蛋白MAP-tau是 轴突变性时裂解的脑组织。我们开发了一种灵敏的酶联免疫吸附试验 特异地量化这种神经元变性的生物标志物，裂解tau (C-tau)。我们的初步研究表明，C-tau水平增加 在B组链球菌脑膜炎(GBM)的动物模型中增加300倍以上。我们 将利用GBM众所周知的神经毒性来验证C-tau是一种 神经毒性的生物标记物和神经保护剂有效性的衡量标准。我们的 具体目标是： 具体目标1：确定GBM是否导致随时间变化的 脑、血浆和脑脊液中C-tau的浓度。 特定目标2：测定脑、脑脊液和血浆中C-tau的水平 与传统的基底膜神经元损伤测量方法相比较。 具体目标3：确定周围组织，如肝、肾或 脾是GBM中C-tau的潜在来源。 具体目标4：确定已知的神经保护性干预措施是否 在GBM中有效的对C-tau水平具有可预测的影响。 建议的商业应用： C-tau酶联免疫吸附试验可用于量化脑膜炎脑损伤的严重程度，以及在基础科学、临床前和临床研究环境中量化神经保护剂干预的效果。

DESCRIPTION (provided by applicant): The objective of this Phase I application is to develop a sensitive biomarker for quantifying neurotoxicity and neuroprotectant efficacy in meningitis. Previous research documents that brain injury caused by meningitis affects multiple brain areas with a heterogeneous distribution. We have previously shown that the cytoskeletal protein MAP-tau is cleavedin brain during axonal degeneration. We developed a sensitive ELISA that specifically quantifies this biomarker of neuronal degeneration, cleaved-tau (C-tau). Our preliminary studies demonstrate that levels of C-tau are increased over 300-fold in an animal model of group B streptococcus meningitis (GBM). We will use the well-documented neurotoxicity of GBM to validate the C-tau as a biomarker of neurotoxicity and a measure of neuroprotectant efficacy. Our Specific Aims are: Specific Aim 1: Determine whether GBM results in a time-dependent elevation in brain, plasma and CSF concentrations of C-tau. Specific Aim 2: Determine it C-tau levels in brain, CSF and plasma correlate with traditional measures of neuronal damage in GBM. Specific Aim 3: Determine whether perihperal tissues such as liver, kidney or spleen are potential sources of C-tau measured in GBM. Specific Aim 4: Determine whether a neuroprotectant intervention known to be effective in GBM has predictable effects on C-tau levels. PROPOSED COMMERCIAL APPLICATIONS: The C-tau ELISA may be used to quantify the severity of brain injury in meningitis and to quantify the effects of neuroprotectant interventions in basic science, preclinical and clinical research settings.