CD8+T细胞在脑缺血再灌注后切割c-FN诱导小胶质细胞-神经元的“过度”交互调控导致BBB破坏

脑梗死后经溶栓/取栓治疗血管开通率可达70-80%，然而50%患者加重甚至死亡是临床面临的难题，恶性脑水肿可诱发脑疝是早期死亡原因之一。本项目基于已建立的临床队列，将NIHSS15-20分溶栓患者DSA验证血管再通后，分为恶性脑水肿组（有中线偏移）和非恶性脑水肿组，行高蛋白测序筛选出与恶性脑水肿密切相关的纤维连接蛋白（FNs）。并发现再灌注后1h是外周血CD8+T细胞随血流进入梗死区域，携带的GZMB切割c-FN超早期破坏BBB，同时诱导了小胶质细胞与神经元"过度"交互调控，导致内源性IL-1β/GZMB切割c-FN的“恶性循环”协同下游机制，持续破坏BBB，是形成恶性脑水肿的分子机制。拟验证GZMB作为治疗靶点的可行性，探讨基于病理改变的产物FN-复合物对脑水肿进展的预测作用，有临床转化价值。本项目是上一国家自然基金项目的延续，拟发表SCI论文3-7篇,申请专利1项。

Malignant cerebral edema induced by ischemic stroke is one of the main causes of early death. Applicant committed to brain edema and blood brain barrier (BBB) study and published 10 SCI papers (including 1 paper IF＞10 ).We have a good understand of this field. This project is a continuation of last national natural fund project. On the basis of clinical data, we screened and confirmed FN was closely associating with malignant brain edema. We found that after ischemia reperfusion peripheral blood CD8 + T cells increased within 1h and triggered the intracranial environment "vicious cycle" of cleaving c-FN by IL-1/GZMB/c-FN. This is the cause of early BBB destruction and brain edema after ischemia reperfusion. In this project, we verified the feasibility of GZMB as a therapeutic target and established an early warning model of BBB damage based on pathological changes, which has clinical conversion value. We plan to publish 3-7 SCI papers, educate Ph.D. students 2-3 doctoral students and apply for patents base on this project. We plan to do truly meaningful basic research and clinical trials for early warning and intervention of BBB damage after ischemia reperfusion.