基于蛋白质构象病新概念新策略探索疏肝解郁法干预AD核心病理产物的分子机理

The new concept of conformational disease takes international molecular medicine into a new generation.The new proposed intervention strategies provide more feasibility for curing major conformational diseases.Alzheimer's disease (AD) is a typical neurodegenerative conformational disease. At present, there is no any progress on the pathological process which is continuing deterioration. We think that the Gan-Yu is the originating mechanism of AD in Chinese medicine, and firstly proposed a new theory hypothesis, "the Liver-Depression( Gan-Yu ) should be associated with ER Stree (ERS) ", which is based on the new concept of conformational disease and the series research results achieved through intervening this disease by ShuGanjieyu prescription. It is found that AD characteristics pathology products, beta-AP and phosphorylated Tau protein, were significantly reduced by using this prescription. However, its molecular mechanism is needs to be revealed. Therefore, intervention role of ShuGanjieyu prescription Act10 molecular target points will be systemic researched by selecting variety cells and animal pathology models. Act10 molecular target points are critical roles for cell autophagy and ubiquitin-proteasome system (UPS) and maintaining cell normal structure. The effects of ShuGanjieyu prescription on activities of two mainly mistake protein degradation system and the stabilization of cell structure are firstly discussed. The key molecular mechanism of intervening AD core pathology products is explored. These results provide scientific basis for its clinical intervention AD and blaze new trail in the treatment of AD by Traditional Chinese Medicine.

构象病新概念是近年国际分子医学发展的重要里程碑，据此提出的干预治疗新策略对诸多重大疑难构象病可能具有根治性的意义。阿尔茨海默病（AD）是一种典型的神经变性构象病，目前对其持续恶化的病理进程一筹莫展。多年来我们基于AD中医肝郁始发病机认识和首次立足构象病概念提出的“肝郁-内质网应激（ERS）关联”理论新假说，以疏肝解郁法干预本病取得了系列研究成果，发现该方可显著降低AD特征性病理产物β-AP和磷酸化Tau蛋白，但其分子机制尚有待揭示。鉴此，本项目拟基于现有研究基础和构象病干预新策略，系统研究疏肝解郁法对细胞自噬、泛素-蛋白酶体系统（UPS）及对维持细胞结构稳定起关键作用的Actin分子靶点的干预作用，首次探讨疏肝解郁法对细胞内二个主要错误蛋白质降解体系的活性及细胞结构稳定的影响，阐明其干预AD核心病理产物的关键分子机制，为其临床干预AD提供科学实验依据，并为本病中医药防治研究开辟新思路。

构象病新概念是近年国际分子医学发展的重要里程碑，据此提出的干预治疗新策略对诸多重大疑难构象病可能具有根治性的意义。阿尔茨海默病（AD）是一种典型的神经变性构象病，目前对其持续恶化的病理进程一筹莫展。多年来我们基于AD中医肝郁始发病机认识和首次立足构象病概念提出的“肝郁-内质网应激（ERS）关联”理论新假说，以疏肝解郁法干预本病取得了系列研究成果，发现该方可显著降低AD特征性病理产物β-AP和磷酸化Tau蛋白，但其分子机制尚有待揭示。本项目首先通过网络药理学分析发现疏肝解郁代表方——柴胡疏肝散通过多条通路作用于细胞的基因转录表达、信号转导、细胞增殖、凋亡、炎症、血管新生等生物过程，从而发挥抗AD作用。接下来采用分子生物学实验进行验证，发现柴胡疏肝散能通过拮抗内质网应激通路抑制海马神经元细胞凋亡，也能通过Notch1信号通路改善大脑神经可塑性从而发挥抗抑郁作用。此外，柴胡疏肝散能通过上调pAkt水平，下调Bax水平减少β淀粉样蛋白诱导的神经细胞死亡，通过促进自噬体形成和溶酶体数目和功能加强对损伤细胞和毒性蛋白的清除。本项目阐明了疏肝解郁法干预AD的分子机理，为其临床干预AD提供科学实验依据，并为本病中医药防治研究开辟新思路。