环境毒素联合VMAT2遗传操控建立帕金森病动物模型的研究

帕金森病（PD）是病因未明的常见神经变性病。现有的神经毒素和遗传模型都未能充分反映PD的年龄、遗传和环境因素交互作用的发病特征，已成为制约PD研究进步的主要障碍之一。建立能更好模拟PD发病机制的动物模型是该领域亟待突破的问题。研究表明，降低VMAT2表达至正常5%水平的基因敲低小鼠可以较全面呈现PD的运动、非运动症状和α-突触核蛋白聚集病理，但耗时长达28个月。本课题拟在细胞、线虫和小鼠中，探索敲低VMAT2表达联合我们在临床上首次发现并经过体内外研究验证的新环境毒素甲氰菊酯或经典毒素鱼藤酮为促发因素，建立一种融合年龄、以VMAT2敲低为遗传背景、甲氰菊酯或鱼藤酮慢性暴露为诱因的PD模型，通过行为学、组织病理、神经生化和分子生物等方法验证模型的可靠性，旨在弥补现有模型的不足，为进一步研究PD的发病机制和疾病修饰治疗提供快速稳定且能更好模拟人类PD发病过程的模型，推动PD研究的进步。

Parkinson's disease (PD), the etiology of which remains unknown, is a common neurodegenerative disorder that seriously affects the sufferer's quality of life. None of the current neurotoxin-based or genetic-based animal model of PD recapitulates aging-gene-environment interaction pattern of PD pathogenesis, which becomes a conspicuous issue that halts the progression of PD research. Model that could better mimic the etiology and pathogenesis of PD is needed urgently to overcome the bottleneck of PD research. It has been indicated that transgenic mice which remain 5% of VMAT2 protein activity present the motor-, non-motor symptoms and pathology of α-synuclein accumulation, but only at 28 months old or elder. Furthermore, in our PD clinic, we found a PD patient who has experienced a history of eating fenpropathrin-poisoned fish for half a year. Subsequently, we laboratorily confirmed the positive correlation between fenpropathrin and PD in dopaminergic cell cultures, mice and rats. In this study, we propose to develop PD models based on ageing, VMAT2 gene susceptibility and chronic fenpropathrin or rotenone exposure in dopaminergic cell lines, caenorhabditis elegans and mice. The behavior assessments, brain histology, peripheral toxicity, biogenic amine levels in the striatum, the ultrastructural changes of the SNpc, and the oxidative stress levels of the midbrain are employed to verify the reliability of these models. We aim to establish a reliable and more clinically-related model, which could overcome the limitations of current PD models and promote the progression of PD research, especially for the pathogenesis and disease-modifying treatment research of PD.