脑血管再生修复的细胞和分子基础

To aim at the points "blood vessel regeneration" and "animal models of human vascular diseases" in the annual guide, this project will use zebrafish as the major model system, together with some mouse and rat studies. we will first establish zebrafish models for two types of human cerebrovascular diseases, death of regional cerebrovascular network and blood vessel rupture. Using high resolution live imaging and other techniques, this project will focus on the dynamic cellular events and molecular mechanisms of two processes, cerebrovascular regeneration and repair of cerebrovascular rupture. This project includes the following four specific aims. 1) Identifications of key cell types for the cerebrovascular regeneration and live imaging of the dynamic cellular events. 2) Identifications of key factors and molecular mechanisms of the cerebrovascular regeneration. 3) Identifications of key cell types for the repair of cerebrovascular rupture and single-cell resolution live imaging of the dynamic cellular events. 4) Identifications of key factors and molecular mechanisms of the cerebrovascular rupture repair. These studies will lead to novel insights into the cerebrovascular regeneration and repair.

针对本年度指南重点资助第（一）部分第6个研究方向中的“血管细胞的再生”和第（二）部分第4个研究方向“模拟人类血管疾病的动物模型”，本项目拟以斑马鱼为模式动物，辅以小鼠和大鼠模型，通过建立局部脑血管网坏死和脑血管破裂两种不同类型人类脑血管疾病的斑马鱼模型，致力于从以下四个部分研究局部脑血管网再生重构和脑血管破裂后修复的动态细胞过程，鉴定这两个过程各自的关键调控因子并揭示其发挥功能的分子机理：1）局部脑血管网再生重构过程的动态实时观察及重要功能细胞的鉴定；2）局部脑血管网再生重构关键调控因子的鉴定及其功能机制研究；3）脑血管破裂修复过程的动态实时观察及关键修复细胞的鉴定；4）脑血管破裂修复关键调控因子的鉴定及其功能机制研究。

本项目顺利完成任务书中各项研究计划，主要包括：1）建立了斑马鱼局部脑血管网损伤后再生模型，运用该模型发现发现局部脑血管网损伤后，脑膜淋巴管短暂进入受损脑区以排除损伤导致的脑水肿，并引导和帮助脑血管再生。2）发现趋化因子Cxcl12b/Cxcr4a是脑膜淋巴管进入受损脑区的关键引导因子，决定脑膜淋巴管及其引导的新生血管的生长方向。3）发现巨噬细胞在脑部微血管断裂修复中的新功能，可通过物理粘附血管断点并产生机械收缩力直接修复断裂脑微血管。4）发现断点内皮细胞释放的ATP在巨噬细胞识别血管断点过程中发挥重要功能。