中西医结合防治神经退行性疾病
氧化代谢紊乱、氧自由基产生增加、免疫/炎症反应是氧化代谢紊乱引起的神经元死亡的重要病理生理过程；内质网应激、未折叠和错误折叠蛋白累积是参与氧化代谢紊乱引起的神经元死亡的主要细胞机制。氧化代谢紊乱通过调节RNA编辑参与代谢型谷氨酸受体mRNA剪切过程，从而改变神经元代谢型谷氨酸受体的钙通透能力、引起细胞钙调节功能紊乱，导致神经元死亡。中药在抗氧化、抗自由基和抗炎等方面有广泛的活性，在传统中药中可以寻找延缓老年性神经退行性疾病发展的生物活性小分子和中药复方，可为防治老年性神经退行性疾病，尤其是阿尔茨海默病提供策略和方法。
神经退行性疾病关键靶标的分子调控机制研究
在中药包公藤中发现具有莨菪烷母核的天然拟胆碱药包公藤甲素，而传统上阿托品等天然莨菪烷类均呈现完全相反的抗胆碱活性。以包公藤甲素为模板，设计并合成系列衍生物，评价其对M胆碱受体的亲和力及内在活性，结合分子对接、定量构效关系、分子动力学模拟等计算机模拟方法，阐明天然拟/抗胆碱药中莨菪烷母核的构效关系。筛选获得结晶，解析受体与包甲素衍生物/阿托品复合物的三维结构，阐明莨菪烷母核在激动/拮抗M胆碱受体过程中可发挥相反活性的结构生物学机制。
基于表面等离子共振分析和临近标记技术的靶标发现研究
在大量天然药物中，有些药物的细胞水平活性乃至动物水平活性均很确切，但作用靶点未知，寻找特异性靶点是天然药物研究的重点和难点。SPR技术联合MS可以从特定细胞或组织中富集靶蛋白并可分析出靶蛋白序列和丰度信息，该方法具有实时可视且特异性高的特点，对于活性明确、靶点亲和力高的天然产物尤为适用。临近标记技术可以进一步在药物靶点被探知的情况下高效地筛选出靶点下游信号转导的相关蛋白，对于阐明天然产物作用的机制至关重要。
Combination of traditional Chinese and western Medicine to prevent and treat neurodegenerative diseases
Disorders of oxidative metabolism, increased production of oxygen free radicals, and immune/inflammatory reactions are critical pathophysiological processes of neuronal death caused by disturbances of oxidative metabolism, endoplasmic reticulum stress, accumulation of unfolded and misfolded proteins are involved in the nerves caused by disturbances of oxidative metabolism—the primary cellular mechanism of meta-death. Disorders of oxidative metabolism participate in the splicing process of metabotropic glutamate receptor mRNA by regulating RNA editing, thereby changing the calcium permeability of neuronal metabotropic glutamate receptors, causing cellular calcium regulation dysfunction and leading to neuronal death. Traditional Chinese Medicine has a wide range of activities in terms of anti-oxidation, anti-free radical and anti-inflammatory. In Traditional Chinese Medicine, small biologically active molecules and traditional Chinese medicine compounds that delay the development of senile neurodegenerative diseases can be found to prevent and treat neurodegenerative diseases, mainly Alzheimer's disease.
Research on the molecular regulation mechanism of crucial targets in neurodegenerative diseases
In the Traditional Chinese Medicine Baogongteng, the natural cholinergic drug Baogongteng-A with tropane scaffold was found. Traditionally, natural tropane compounds, such as atropine, have anticholinergic activities. Using Baogongteng-A as a lead, a series of derivatives could be designed, synthesized and evaluated. By using molecular docking, quantitative structure-activity relationship, molecular dynamics simulation, the structure-activity relationship of tropane scaffold could be elucidated. With crystal structures, the structural, pharmacological mechanism of the tropane scaffold activity would be clarified.
Target discovery based on surface plasmon resonance analysis and proximity labelling technology.
Among many natural products, some showed exact bioactivities at the cellular level or even in animals, but the targets are largely unknown. Finding specific targets is a difficult task of natural medicine research. SPR technology combined with MS can enrich the target protein from specific cells or tissues and analyze the sequence and abundance information of the target protein. This method has the characteristics of real-time visibility and high specificity. Proximity labelling technology can further efficiently screen out the relevant proteins for signal transduction downstream of the target, which is essential for elucidating the mechanism of natural products.