Biomarker of Neuroprotectant Efficacy

说明(由申请人提供)：第一阶段可行性的目标 研究开发一种灵敏的生物标志物来定量神经保护药物 在创伤性脑损伤(TBI)大鼠模型中的疗效。目前，没有广泛的 公认的量化大鼠脑外伤模型神经元损伤的生化标记物 是可用的。我们之前已经证明，在轴突变性过程中 人类的大脑细胞骨架蛋白图谱-tau是裂解的。我们的实验室有 开发了一种灵敏的酶联免疫吸附试验，专门测定裂解的MAP-tau(C-tau) 在颅脑损伤后的人脑脊液中。使用这个酶联免疫吸附试验，我们已经证明了大脑 持续皮质冲击性脑损伤后大鼠c-tau水平升高。通过 在测量病变体积时，Schef等人先前已经证明 颅脑损伤后应用环孢素A显著改善皮质 皮质撞击大鼠模型的损伤。我们假设C-tau是一个 脑外伤大鼠神经元损伤的可靠生物标志物。我们将对此进行测试 通过确定C-tau水平是否表现出时间依赖性的增加来进行假说 在脑外伤后，如果已知的神经保护剂干预，环孢素A，施加 对C-tau水平的预期影响。我们的具体目标是： 具体目标1：确定TBI是否导致随时间增加的 大脑中C-tau的水平。受脑损伤影响的患者c-tau水平将通过酶联免疫吸附试验进行定量 控制大脑区域，也控制假手术动物的大脑区域。具体目标2： 确定C-tau水平是否可靠地量化已知的 脑外伤的神经保护性干预。环孢素的神经保护作用 将通过使用赋形剂或环孢素A进行检查。 在脑损伤诱导的C-tau达到最大值时，将通过酶联免疫吸附试验定量 在特定目标1中确定的海拔高度。C-tau水平将作为 神经保护性治疗的作用。

DESCRIPTION (provided by applicant): The objective of this Phase I feasibility study is to develop a sensitive biomarker for quantifying neuroprotectant drug efficacy in a rat model of traumatic brain injury (TBI). Currently, no widely accepted biochemical marker that quantifies neuronal injury in rat TBI models is available. We have previously shown that during axonal degeneration in humans, the brain cytoskeletal protein MAP-tau is cleaved. Our laboratory has developed a sensitive ELISA that specifically measures cleaved MAP-tau (C-tau) in human CSF following head injury. Using this ELISA, we have shown that brain C-tau levels increase in rats after sustaining cortical impact-induced TBI. By measuring lesion volumes, Scheff et al have previously demonstrated that cyclosporin A administration following TBI significantly ameliorates cortical damage in the cortical impact rat model. We hypothesize that C-tau is a reliable biomarker of TBI-induced neuronal injury in rats. We will test this hypothesis by determining if C-tau levels demonstrate a time-dependent increase after TBI and if a known neuroprotectant intervention, cyclosporin A, exerts expected effects on C-tau levels. Our Specific Aims are: Specific Aim 1: Determine whether TBI results in a time-dependent increase in brain levels of C-tau. C-tau levels will be quantified by ELISA in TBI-affected and control brain regions and also in sham operated animals. Specific Aim 2: Determine if C-tau levels reliably quantify the effect of a known neuroprotectant intervention on TBI. The neuroprotective effect of cyclosporin A will be examined by administering either vehicle or cyclosporin A. C-tau levels will be quantified by ELISA at the time of maximum TBI-induced C-tau elevation determined in Specific Aim 1. C-tau levels will be compared as a function of neuroprotectant treatment.