Haptoglobin，运动激活脑缺血后神经保护与康复的潜在靶点？

Our previous study showed systemic exercise conditioning provides neuroprotection from cerebral ischemia and improves neurological function recovery after brain injury. Further studies on serous proteomic in rats with long-term exercise conditioning via classified protein mass spectrometry showed exercise conditioning up-regulate Haptoglobin level in serum. The protein function network analysis also suggested highly functional relevance of Haptoglobin to other proteins which vary in exercise conditioning. Furthermore, the hepatic mRNA level of Haptoglobin significantly increased in exercise conditioning group. We predicted that the “from-whole-to-part” mechanism concerns the changes of blood contents. It was told from literature that Haptoglobin involves in acute phase responses including inflammation and cell apoptosis, which is close related to the occurrence and progression of various nervous system disease. Therefore, serous Haptoglobin may be the potential target of exercise conditioning activating neuroprotection and neurorehabilitation after cerebral ischemia. That is exercise conditioning → serous Haptoglobin up-regulation → inflammation and cell apoptosis inhibition → brain-blood barrier preservation → neuroprotection and neurorehabilitation. To verify the hypothesis, we are going to testify and further explore the down-stream mechanism of in vivo and in vitro effect of Haotoglibin regulated by exercise conditioning on neuroprotection and neurorehabilitation, through morphology, ethology, as well as detection of cell signal molecules concerning inflammation and apoptosis, by using gene knock-out and interference technology.

全身康复运动干预能产生脑缺血保护及损伤神经功能康复已被学界公认。这一“整体→局部”作用可能与血液有关，我们利用蛋白质谱技术发现，运动能显著上调血液中Haptoglobin（Hp）蛋白水平，功能网络分析显示其与其它相关差异蛋白功能关联密切；且，运动组中Hp mRNA转录合成水平也显著增高。Hp蛋白被报道参与急性期反应时调控炎症反应与细胞凋亡，与多种神经系统疾病发生发展密切相关。由此推测，血清Hp蛋白可能是运动干预激活神经保护和康复的潜在靶点！即“运动干预→AMPK激酶通路→转录因子→血液Hp上调/中和血红蛋白→抑制炎症反应/细胞凋亡/血脑屏障破坏→神经保护康复”。为验证此假设，拟通过在、离体研究，利用基因敲除、过表达等技术，从形态学、行为学、炎症、信号通路和转录因子启动子等方面，进行多角度运动调控Hp蛋白的神经保护与康复作用的上下游机制研究。

脑血管疾病是严重危害人类健康的最常见疾病之一，其中缺血性脑卒中占脑血管疾病总发病率的 80%左右。根据全国第三次死因回顾抽样调查报告，脑血管病已跃升为国民死亡原因的首位。不仅如此，脑血管疾病还是导致功能障碍的主要原因，对患者本人、家庭、社会造成巨大负担。有关脑缺血后神经保护策略的探索，已成为缺血性脑损伤防治的研究热点，对脑卒中后的病理生理机制、血流动力学变化的探究是研究脑卒中后康复干预的基石。为此本课题主要关注脑血流重建，并研究运动干预及运动预干预对脑基础血流和脑功能血流的影响。我们严格遵循随机、盲法、对照、重复四大原则，排除实验中的偏倚因素，力求实验结果的科学性和准确性。在项目执行年限中完成了以下研究：在大鼠脑缺血再灌注（MCAO）模型上，利用激光散斑对比成像技术研究了超早期再灌注时的脑血流演变过程，确定了运动预干预对缺血性卒中后脑血流重建的神经保护机制；在大鼠MCAO模型上，确定了短暂性脑缺血发作（TIA）对后续再发的永久性脑卒中具有预处理作用。得到了以下重要结果：从血流动力学上证明运动预处理可降低再灌注超早期动脉和静脉的血流灌注，提示运动预处理可诱导神经保护，可作为一种神经保护策略。首次探讨先发性TIA对复发性脑卒中的调节作用，从不同的病灶位置得出了一个有趣现象，并从分子、形态、功能水平，验证了同侧短暂性脑缺血发作（TIA）对后续再发的永久性脑卒中具有预处理作用。以上研究为脑卒中后防治提供了脑血流重建的证据，为后续研究运动康复的机理打下了良好基础。