基于硝化应激信号网络调控的脑卒中治疗药物靶标发现与药理学确证

The incidence and mortality from stroke is high in China and it causes disability in more than half of stroke survivors in China. However, effective pharmacological therapeutic drugs are still lacking. For instance, the candidate agents that target neurons have failed to show clinical benefit, suggesting that neuroprotective strategy alone is not sufficient in counteracting multiple etiology, multicellular and complex interactions in the pathogenesis of stroke. We previously reported that nitrosative stress can damage biomolecules and subsequently cause the breakdown of neurovascular cellular machinery during the onset and development of ischemic cerebrovascular disease. Recently, the data from URICO-ICTUS trial reported that inhibition of nitrosative stress may prevent early ischemic worsening after acute stroke in thrombolysed patients. In the present project, we set out to address the potential mechanisms of nitrosative stress signaling during pathological process of neurovascular unit damage. Furthermore, we aim to discover and validate the neurovascular protective lead compounds against multiple events of the ischemic injury cascade, by targeting key players in nitrosative stress pathway, such as calmodulin, E6AP and GPR124 as well. Moreover, accessible novel biomarkers of neurovascular fragility and of released cytotoxins will be discovered. The clinical validation of the proof of concept, followed by the assessment of safety and efficacy of nitrosative stress signaling repurposed drugs will definitively offer new opportunities for the acute treatment of ischemic stroke.

脑卒中已成为我国第一大致死、致残的疾病，但目前临床尚缺乏疗效确切的治疗药物。“单独神经元保护候选药物”的失败提示该策略不能反映“多病因、多细胞、复杂交互”的脑卒中病理过程。我们前期深入研究发现：在缺血性脑血管病病理过程中，硝化应激信号是介导脑微血管损伤的关键分子事件。临床研究报道也提示外源性抗硝化应激药物能够减轻脑卒中患者早期临床恶化发生率。因此，本项目以硝化应激信号为“切入点”，以脑微血管损伤-胶质细胞激活-神经元死亡因果链为“探索路径”，深层次探讨神经血管单元损伤的机制。以酶活性和受体调控理论为指导，以脑保护为药效评价“终点”，系统地开展基于硝化应激信号网络调控的脑卒中靶标研究，筛选出以该信号网络关键节点为靶标（Calmodulin、E6AP、GPR124等）的新型先导化合物。在分子、细胞和整体动物水平研究该类化合物药理活性并阐明机制，系统性确证药理活性与靶标相关性。

脑卒中是危害我国人民健康的重大疾病，但目前临床仍缺乏疗效确切的治疗药物。基于硝化应激分子事件的“多病因、多细胞、复杂交互”是脑卒中重要病理特征。本项目以硝化应激信号为“切入点”，以脑微血管损伤-胶质细胞激活-神经元死亡因果链为“探索路径”，深层次探索了神经血管单元损伤的机制。以临床问题为指导，以脑保护为药效评价“终点”，系统地开展了基于硝化应激信号网络调控的脑卒中靶标研究，在分子、细胞和整体动物水平对硝化应激信号网络关键节点（Calmodulin、E6AP、GPR124等）进行了机制研究和靶标确证。本项目在阐明脑卒中病理机制基础上为该疾病的药物靶标发现提供了重要依据和理论基础。