TSPO-P47phox/P22phox-NF-kB轴调节小胶质细胞表型转化及其在帕金森疾病中的作用研究

帕金森疾病(PD)是常见的神经退行性疾病，大量研究表明小胶质细胞表型转化在PD发病过程中发挥重要作用。18kDa转运蛋白(TSPO)是位于胶质细胞线粒体外膜蛋白，可作为神经炎症标志物并抑制神经炎症，但机制不明。有报道过表达TSPO可抑制小胶质细胞NF-kB转录活性，使其表现为M2型，然具体机制不明。而NADPH氧化酶是小胶质细胞表型转化关键因素。前期研究发现TSPO可促进PD模型鼠M2型细胞因子表达，减轻多巴胺神经元损伤，进一步发现TSPO抑制NADPH氧化酶活性且直接抑制P47phox与P22phox结合。我们推测：TSPO通过抑制P47phox/P22phox-MAPK-NF-kB介导小胶质细胞表型转化，从而影响PD病理过程。本课题拟用靶向成像与分子生物学等技术研究TSPO对小胶质细胞表型变化的调节机制，揭示其在抗PD治疗中的作用和意义，为开发针对TSPO特异性配体的靶向药物提供依据。

Parkinson’s disease (PD) is a common neurodegenerative disease. Microglial phenotypes have been recognized play an important role in Parkinson’s disease (PD)pathology. Translocator protein 18 kDa (TSPO) is a mitochondrial outer membrane protein. Although TSPO expression is up-regulated during neuroinflammation, the role of TSPO and its signaling mechanisms in regulation of neuroinflammation remains to be elucidated at the molecular level. TSPO is reported by increased expression of alternatively activated M2 stage related, which is partially mediated by the attenuation of NF-κB activation. NOX activation is critical factor in regulating microglial/macrophage polarization.In the present study, we found the regulating effects of TSPO on microglia-mediated NADPH oxidative activity,promote M2 polarization and decrease dopaminergic neuron loss. we examined whether there is physical association between the TSPO and NADPH oxidase. We found that TSPO increase interaction with p47phox,but decrease P47phox/P22phox interaction. We propose that a TSPO interaction with cytosolic P47phox to decrease P47phox/P22phox –MAPK-NF-kB signal pathway in the induction of an M2response to maintain neuroprotection. So we intend to use PET imaging and molecular biological technicals to discuss the mechanisms of TSPO functions in parkinson’s disease. The investigation contributes to clarify the roles of TSPO in the pathologic process of parkinson’s disease. These works will give us a novel insight into thetargeted drug of TSPO.