世居高原藏族脑结构和功能适应神经影像及相关基因机制研究

项目名称： 世居高原藏族脑结构和功能适应神经影像及相关基因机制研究

项目编号： No.81471630

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张家兴

作者单位： 厦门大学

项目金额： 73万元

中文摘要： 高原低氧适应关系到高原人类的生存。世居高原藏族在循环、呼吸和血液系统获得了最佳适应。然而，脑如何重塑来调节这些系统的活动目前尚不清楚。近年高原研究最重要进展是揭示了藏族适应的遗传学机制，发现EPAS1、EGLN1和PPARA基因单核苷酸多态性（SNP）与高海拔低氧适应有关。本项目首先采集多模态脑磁共振数据，通过与匹配的世居低海拔藏族比较，观察世居高原藏族脑灰质和白质体积、皮层厚度、静息态和任务态局部神经细胞活动及结构和功能网络的重塑特征；其次，分析候选EPAS1、EGLN1和PPARA基因SNP与重塑脑区结构和功能的相关性；最后，选择与高原藏族脑重塑相关性最显著的2个SNP，制备单基因和双基因突变小鼠模型，用来验证人体脑研究结果，并探讨皮质和髓质内细胞和血管构筑及调控神经和血管发生的分子信号通路。本项目将在器官、组织和分子水平揭示世居高原藏族低氧脑适应性重塑的特征及其基因调节机制。

中文关键词： 高原适应；高原低氧；低氧诱导因子；脑；磁共振

英文摘要： Hypoxic adaptation is of critical importance for human survival at High altitude (HA). Tibetan natives at HA have developed optimal adaptations in the circulation, respiration, and blood systems. However, how the brain in Tibetan natives through modulating its structures and functions to regulate the activities of these systems remain still unclear. In recent years, the most important progress is the clarification of the mechanisms underlying Tibetan's adaptation to HA, showing the EPAS1, EGLN1 and PPARA gene SNPs were related to HA adaption. In the present study, multiple MRI data were first used to study brain gray matter and white matter volumes, cortical thickness, resting-state and task-activated neuronal activity, and structural and functional networks in Tibetan natives at Qinghai-Tibet Plateau. Control subjects were matched lowland Tibetan natives. Second, the correlations between SNPs of EPAS1, EGLN1 and PPARA gene and brain modifications were analyzed. Finally, two SNPs, which showing most correlations with Tibetan native brain modifications, were mutated in mice. These gene mutant mice were used for verifying brain modifications in Tibetan native, detecting the constructions of cells and blood vessels in the brain, and exploring the signal pathway that regulating neurogenesis and angiogenesis. The present study will clarify brain modifications and the mechanisms underlying these alterations in Tibetan native under HA hypoxia environ in the organ, tissue, and molecular level.

英文关键词： high altitude adaptation;high altitude hypoxia;hypoxia inducible factor;brain;MRI