衰老细胞在朊病毒病中的作用和分子机制

神经退行性疾病严重危害人类健康，至今不可治愈。随着年龄增长，脑内衰老细胞的积累在神经退行性病变中起着重要作用。朊病毒病是一类特殊的神经退行性疾病，衰老细胞在朊病毒病中的作用和分子机制尚不清楚。申请人在前期研究基础上，提出朊病毒感染引起脑内衰老细胞富集，加剧神经炎症，并由此加重病理特征、加快发病进程的假说。为此，计划以朊病毒感染小鼠为模型，首先检测脑内衰老细胞标志基因是否上调及发生衰老的细胞类型。再通过衰老细胞裂解药物或化学遗传学方法清除衰老细胞，或采用细胞衰老调控基因敲除小鼠，分析小鼠的生存曲线、行为学和病理特征，明确衰老细胞对朊病毒病的作用。再运用高通量RNA测序，检测小鼠脑内衰老细胞被清除后基因表达的变化，建立相关图谱和信号通路，阐明衰老细胞在朊病毒感染引起的神经病变中的分子机制。预期本项目可望为探索以衰老细胞为靶标的朊病毒病及其他神经退行性疾病的治疗方法提供新的思路。

Neurodegenerative diseases are a group of debilitating disorders characterized by the progressive degeneration of the structure and function of the central nervous system(CNS). They are incurable by far. The accumulation of the senescent cells in the CNS with aging plays an important role in the pathogenesis of neurodegeneration. Prion diseases are a type of unique neurodegenerative disorders because of their transmission between individuals, the role and molecular mechanisms of senescent cells in prion pathogenesis remains unknown. Based on our previous study on prion diseases, we propose a hypothesis that prion infection induces an accumulation and enrichment of senescent cells in the CNS, thereby enhancing the neuroinflammation and deteriorating neuropathology, leading to an acceleration of prion progression. To verify this hypothesis, we plan to apply a mouse model of prion infection and test whether senescent cell markers are upregulated and which cell types show senescent phenotype in the brain. We will then remove the senescent cells from the brain by senolytic compounds (navitoclax/ABT-263) or through a genetic approach (INK/ATTAC - AP20187 system), or employ a gene knockout mouse that controlling the cell senescence, to assess the survival curves, behavior and pathological changes, and finally determine role of senescent cells in prion pathogenesis. We will perform RNA sequencing to dissect the molecular mechanisms underlying how senescent cells affect prion pathogenesis and establish the cascade and pathways of the mechanisms. We expect our study will bring new knowledge and insights to explore novel therapeutic avenues for prion disease and other neurodegenerative disorders by targeting senescent cells.