髓样分化因子88调控中枢兴奋毒性易感性的机制研究

Massive glutamate release-induced central excitotoxicity is a pivotal event leading to brain ischemic injury. Therefore, elucidating the mechanisms underlying glutamate excitotoxicity during brain ischemia is of particular importance to the research field. Neurons in different areas of the mammalian central nervous system (CNS) exhibit differential tolerance to glutamate excitotoxicity, suggesting there are brain area-specific pro-death and pro-survival signals. We have found that myeloid differentiation primary response gene 88 (MyD88), a key adaptor for Toll-like receptors in the innate immune system, is differentially expressed in the brain. The expression level of MyD88 correlates well to its protection against cerebral ischemia-induced neurodegeneration, suggesting MyD88 is an endogenous pro-survival molecule in the brain. MyD88 deficiency leads to enhanced ischemic injury in a manner independent of the canonical NF-kappaB pathway. MyD88 deletion, however, leads to an accelerated CaMKII re-phosphorylation after excitotoxicity-induced desphoshorylation in the hippocampus. We will further explore the mechanism underlying MyD88-mediated protection against excitotoxicity, with an effort on determining the interaction between MyD88 and CaMKII, to provide fresh insights into the basic and clinical research of cerebral ischemia.

由过量谷氨酸释放导致的兴奋毒性作用是引发脑缺血损伤的重要机制之一，因此深入阐明脑缺血的兴奋毒性机制、寻找参与兴奋毒性的特异性靶点是攻克脑缺血疾病的关键。哺乳类中枢神经系统（CNS）不同区域神经元对于谷氨酸兴奋毒性的敏感程度并不相同，提示CNS存在脑区依赖的促死亡和促生存通路。我们发现先天免疫系统中的重要衔接蛋白髓样分化因子88（MyD88）在CNS不同脑区表达量不同。MyD88在CNS不同区域的表达量和其缺血保护作用成正相关，提示MyD88是一内源性的缺血保护分子。MyD88对兴奋毒性的保护作用与NF-κB及其炎症通路无关，而与维持兴奋毒性诱导的CaMKII去磷酸化态相关。我们将深入研究MyD88介导的缺血保护机制，着重阐明MyD88和CaMKII互作调控中枢兴奋毒性易感性的分子机制，为脑缺血疾病的理论研究和临床诊治提供新的思路。

缺血缺氧性去极化、大量谷氨酸释放以及钙超载是引发脑缺血损伤的一系列重要早期事件。深入阐明脑缺血损伤的早期机制、寻找早期缺血损伤的特异性靶点是攻克脑缺血疾病的关键。哺乳类中枢神经系统（CNS）不同区域神经元对于脑缺血损伤的敏感程度并不相同，提示CNS存在脑区依赖的促死亡和促生存通路。髓样分化因子88（MyD88）是Toll样受体募集的重要衔接蛋白。我们的前期研究发现MyD88在CNS不同脑区表达量不同。MyD88在CNS不同区域的表达量和其缺血保护作用成正相关，这提示MyD88可能是一内源性的缺血保护分子。此项研究中，我们发现1）MyD88可保护神经元抵抗缺血/复灌损伤；2）MyD88通过维持氧糖剥夺（OGD）/复灌早期的钙离子-钙调素依赖性蛋白激酶II（CaMKII）的去磷酸化来降低AMPA受体的Ca2+通透性；3）CaMKII的T286位点的磷酸化是MyD88参与脑缺血损伤保护的关键作用靶点；4）MyD88可能通过与蛋白磷酸酶2B（PP2B）和/或PP1的相互作用来维持CaMKII的去磷酸化从而介导兴奋毒性保护作用。综上所述，我们发现CNS的MyD88可能是针对脑缺血损伤的内源性保护因子，其机制很有可能是通过与蛋白磷酸酶的相互作用来调节CaMKII的自身磷酸化，从而保护神经元免受兴奋毒性引起的损伤。这一发现可为脑缺血疾病的理论研究和临床诊治提供新的思路和潜在的治疗靶点。