CD200R表达调控异常在小胶质细胞激活及帕金森病发病中作用的研究

It has been known that the decreasing of the interaction between CD200 and CD200 receptor (CD200R) would lead to the abnormal activation of microglia and the neuroinflammation in central nervous system. Our previous studies showed that the protein level of CD200R in monocyte-derived macrophages was not efficiently up-regulated in responding to the stimuli in elders especially those suffering Parkinson's disease (PD). In 6-OHDA PD mouse model, the blockage of the interaction between CD200 and CD200R by anti-CD200R blocking antibody could increase the toxic effect of 6-OHDA to dopaminergic neurons, suggesting that the attenuation of the inhibitory signal resulting from the abnormal regulation of CD200R expression may play an important role in the pathogenesis of PD. In this proposal, we are going to identify the promoter region and the regulatory elements of CD200R gene in monocyte-derived macrophages. Based on these, we will continuously investigate the regulation of CD200R expression in microglia and observe the relationship between impaired regulation of CD200R expression and abnormal activation of microglia as well as the degeneration of dopaminergic neurons under the pathological conditions of PD. All these will help us to understand the molecular mechanism underlying the microglial activation and neuronal loss in PD.

CD200、CD200R的相互作用是维持小胶质细胞"静止"状态的重要抑制信号， CD200或CD200R下降都会导致小胶质细胞异常激活和神经炎性反应。我们前期发现老年人特别是PD患者中外界刺激不能上调单核巨噬细胞CD200R的表达；用CD200R封闭抗体阻断CD200、CD200R的相互作用可增强PD动物模型中6-OHDA的神经毒性作用。单核巨噬细胞和小胶质细胞的同源性及一些共同特征提示：上述单核巨噬细胞中CD200R表达调控的异常也可能发生在小胶质细胞,导致其异常激活，最终诱发PD。目前，尚无有关CD200R表达调控的研究。我们将首先在单核巨噬细胞内通过体内外实验明确CD200R的启动子和上游调节因子，在此基础上观察小胶质细胞中CD200R表达的正常调控机制以及PD病理状态下CD200R调控异常与小胶质细胞激活、多巴胺能神经元损伤间的关系，以期阐释小胶质细胞异常激活和PD发生的可能机制。

CD200R作为小胶质细胞激活重要的抑制蛋白，在维持人脑内小胶质细胞稳态中发挥重要作用。而在PD中CD200R表达调控的异常导致小胶质细胞异常激活，从而引起神经元死亡。因此，明确何种原因导致PD中CD200R表达调控异常非常重要。基于此，我们首次鉴定了CD200R启动子区域并筛选出调控其表达的上游转录因子NFKB1，同时在PD患者外周血PBMC中，发现CD200R及NFKB1表达较之正常人均明显下降，且两者的表达存在明显的相关性。此外，在正常人外周血PBMC中我们观察到LPS刺激可上调CD200R表达，而此种现象在敲除NFKB1后受到抑制，表明NFKB1在PD中的下降可能为CD200R表达异常的原因。我们的发现从转录因子调控层面解释了PD中CD200R表达调控异常的原因。该研究结果不仅帮助我们了解CD200R的生物学特性，还帮助我们认识CD200R表达调控异常在PD及其他相关疾病中的可能发病机制，具有一定的普遍意义和研究价值。