周细胞介导的PDGF-BB/PDGFRβ-IL-33/ST2信号通路在帕金森病中的作用机制

帕金森病（PD）是一种严重的神经退行疾病，神经血管单元（NVU）结构和功能障碍在PD发病机制中有重要影响。周细胞作为NVU的核心成分，在PD病理过程中可能发挥关键作用，但具体机制未明。我们前期工作提示，周细胞所在NVU神经元和微循环整体功能的受损，对PD的病理过程产生重要影响；预实验发现6-OHDA作用于NVU体外模型（周细胞与内皮细胞、星形胶质细胞、SH-SY5Y细胞共培养）时，NVU渗透性下降，细胞凋亡增加。进一步结合近年研究，我们提出周细胞可能通过PDGF-BB/PDGFRβ相关信号通路调控PD病理过程的猜想。本项目拟在PD体内/体外模型中，进行周细胞调控NVU稳态及多巴胺神经元退行性变的机制研究，旨在明确周细胞是否通过PDGF-BB/PDGFRβ -IL-33/ST2信号通路调控PD病理机制这一科学问题，从新的角度阐明周细胞参与PD发生发展的机理，为PD的治疗提供新的分子靶点。

Parkinson's disease (PD) is one of the most severe neurodegenerative disorders. The structural and functional impairment of neurovascular unit (NVU) has an important impact on the pathogenesis of PD. Pericyte, one of the key components in the NVU, is considered to play crucial roles in the physiopathological process of PD; however, the specific molecular mechanisms remain unknown. Our previous studies found that the lesion of dopaminergic neurons and microcirculation function of NVU, where the pericytes locate, was involved in the pathological events in PD. Our preliminary experiments found that when 6-hydroxydopamine was subjected to the NVU in vitro model, which was based on the co-cultures of pericytes, endothelial cells, astrocytes and SH-SY5Y cells, the NVU permeability declined and the cell apoptosis increased. Combined with the recent findings of pericyte these years, we infer that pericyte may regulate the NVU function and PD-related neurodegeneration via platelet-derived growth factor (PDGF)-BB/PDGFRβ-IL-33/ST2 signaling pathway. Thus in this project, we aim to investigate the mechanism of pericyte in modulating neurovascular homeostasis and dopominergic degeneration in the PD animal and cell models, in order to answer the scientific question that whether pericyte could modulate neurovascular homeostasis via PDGF-BB/PDGFRβ-IL-33/ST2 signaling pathway and how it play an important role underlying the pathogenesis of PD. In conclusion, this study would provide potential and novel mediators, i.e. pericyte or PDGF-BB/PDGFRβ, a clue for the development of an alternative approach to the treatment of PD.