神经粘附分子CHL1在缺氧性脑损伤中的调节作用及机制研究

In our previous study, we demonstrated as following：(1)We first discovered a new anti-hypoxia injury regulatory mechanism of neural adhesion molecule CHL1 in the regulation of function and activity of the carotid body. CHL1 deficiency specifically exaggerated carotid sinus nerve and enhanced hypoxic ventilatory response to acute hypoxia. CHL1 deletion has a dramatically decreased risk of mortality to acute hypoxia in mice. (2)CHL1 is a negative factors functioning as the activities of carotid body function and ventilatory responses to hypoxia. (3) Preliminary studies indicate that: the function of CHL1 in the hearts and lungs are not very obvious, and the expression is very low, but in various brain regions has a high level of expression and hypoxia lead CHL1 reduced expression in different brain regions. (4) Expression of CHL1 was decreased after OGD-induced neuronal damage. CHL1 deficiency can improve the survival of OGD-Induced neuronal damage. (5)The content of CHL1 in the plasma is increased after hypoxia. These results indicate that the function of CHL1 in anti-hypoxia injury may be closely related to its regulatory role in hypoxic brain injury. Therefore, the project is intended to further clarify CHL1 regulatory role in the development process and mechanism in hypoxic brain injury in mice, CHL1 is a hypoxic brain injury regulatory factors, CHL1 is expected to become a new hypoxic brain injury marker.

前期的主要研究进展: (1)首次发现神经粘附分子CHL1通过影响颈动脉体的功能和活性，适应性地增大颈动脉体的体积-类似于低氧预适应的调节，提高机体急性缺氧下的呼吸频率和肺通气量以对抗急性缺氧引起的损伤，从而提高小鼠的存活率和存活时间。(2)首次证明CHL1是颈动脉体功能和活性的负调控因子。进一步研究发现：(3) CHL1在心、肺中的表达很低，且作用不十分明显； 但CHL1在大脑的各个脑区均有很高的表达；低氧处理后CHL1在不同脑区的表达下调。(4) 体外培养神经元氧糖剥夺后CHL1表达呈时间依赖性下调；CHL1缺失提高氧糖剥夺后神经元的存活。(5)低氧后血浆中CHL1的含量增加。因此，本项目拟明确CHL1在小鼠缺氧性脑损伤发生发展过程中的调节作用及机制，阐明神经粘附分子CHL1是一个新的低氧脑损伤调控因子，CHL1可能成为一个新的缺氧性脑损伤的标志物。

低氧是高原脑水肿发生的主要原因, 也是脑血管疾病所共有的病理生理过程。本课题主要围绕神经粘附CHL1在缺氧性脑损伤中的调节作用展开。研究内容包括：(1) 观察CHL1基因敲除小鼠在慢性低氧下的生理情况。(2) 小鼠急性高原脑水肿动物模型的建立及发病机制的研究。(3) 探讨CHL1在高原脑水肿发生发展中的调节机制。首先, 动态监测低氧7天, 14天和28天小鼠生理变化情况。持续低氧后小鼠血压并无变化, 体重明显下降, 血浆去甲肾上腺素、肾上腺素和多巴胺的含量明显增加, 血红蛋白的含量明显增加。由于高原环境的地域性和特殊性, 国内外高原脑水肿模型研究报道较少, 系统建立了稳定、高效的小鼠高原脑水肿模型, 并提出炎症反应在高原脑水肿发生发展中的控制作用, 相关研究工作发表在J Neurosci Meth(2015), Brain Behavior and Immunity(2017)。急性高原低氧后CHL1的表达明显降低, CHL1敲除小鼠脑含水量无明显变化并减轻了急性高原低氧损伤对小鼠血脑屏障的破坏, CHL1维持内皮细胞间紧密连接及星形胶质细胞的抗炎反应,是高原脑水肿形成和发展的重要内源性调控分子。本研究工作揭示了高原脑水肿发生发展的炎症控制作用,CHL1通过维持细胞连接调节血脑屏障功能的新机制。相关研究工作CHL1作为低氧生物标记分子的应用授权发明专利1项。