急性缺血性卒中发生后缺血时间和程度，影响缺血半暗带的转归，也决定了神经元损伤是否可逆。微循环环境中pH和氧浓度变化是缺氧后的直接反应，与神经元可逆性损伤的阈值相关。本项目在我们前期研究工作基础上，利用pH敏感的聚乙二醇纳米释放系统和氧敏感荧光显示系统，通过动物模型、微探针、pH和缺氧敏感探针和双光子共聚焦显微镜等技术，重点研究：(一)：急性缺血性卒中后微环境微循环障碍程度、pH和氧浓度变化及与之相关的神经元可逆性损伤的阈值，阐述微循环状态与组织可逆性损伤之间的关系；(二)：通过pH敏感阿替普酶纳米释放体系，选择性作用于缺血微循环散在微血栓，靶向释放rtPA，在微环境恢复pH值或氧含量阈值时，研究微循环再通对神经元的功能恢复的有效性和安全性。通过本项目的实施，阐明神经元损伤恢复的阈值及与微循环灌注之间的关系，为扩大缺血性卒中治疗时间窗、改善其预后提供理论和实验依据。

The duration and extent of ischemia after acute ischemic stroke affects the outcome of the ischemic penumbra and determines whether the neuronal damage is reversible. Changes in pH and oxygen concentration in the microcirculation environment are direct responses after hypoxia and are associated with thresholds for reversible neuronal damage. Based on our previous research work, this project utilizes pH-sensitive polyethylene glycol nano-release system and oxygen-sensitive fluorescent display system, pH and hypoxia sensitive microprobes, and two-photon confocal microscopy techniques on animal models, focus mainly on: First, the microenvironment microcirculation disorder, pH and oxygen concentration changes after acute ischemic stroke and its related threshold of reversible damage of neurons, and the relationship between microcirculatory state and tissue reversible injury; second: establishing the pH-sensitive polyethylene glycol-conjugated alteplase nanogels system, which selectively targeting ischemic microcirculation and dissolve microthrombus, to explore the effectiveness of microcirculation reperfusion therapy or restoration of microenvironmental pH value or oxygen content on neuronal functional recovery. Implementation of this project, will elucidated the threshold of neuronal injury recovery and its relationship with microcirculation perfusion, which provides theoretical and experimental basis for expanding the treatment time window of ischemic stroke and improving its prognosis.