针对syk活性抑制的中药小分子物质筛选及其抗气道炎症作用机制研究

Airway inflammation is the pathological basis and essential causes of asthma and other respiratory diseases. However, till now, there still lack of desirable effective therapeutic drugs. Spleen tyrosine kinase (Syk) plays a key role in inflammatory signaling pathways. Previous studies showed that the Syk inhibiting was closely associated with airway inflammation controlling. But its mechanism is not yet clear. Therefore, our study will build a method for rapid screening of Syk protein affinity ingredients from anti-inflammatory Chinese traditional medicines based of Syk-target beads coupled with LC/MS and NMR, which coupled with the Syk-substrate reaction system, to screen the Syk inhibitory activity ingredients. And, by using the techniques of molecular biology, immune cell co-culture and so on, we will investigate the mechanisms of anti-airway inflammation of Syk inhibitory component of traditional Chinese medicine in inflammation in vitro and in vivo models, airway inflammation model of asthma. The study is of great significance on elucidation the relationship of Syk signaling pathway with airway inflammation, and provides new ideas and target for airway inflammation in asthma therapy. Furthermore, it is expected to find a class Syk inhibitory candidates with intellectual property rights, to lay the foundation for further structural optimization and molecular design.

气道炎症是哮喘等呼吸系统疾病的病理基础，是哮喘症状反复发作的根本原因，但迄今为止，临床上仍缺少理想的治疗药物。脾酪氨酸激酶（Syk）是炎症信号通路的关键调控分子，前期研究发现，Syk抑制与气道炎症控制密切相关，然而，其作用机制尚不十分清楚。因此，本项目拟以抗炎中药为基源，基于Syk靶标磁珠与LC/MS、NMR技术联用，构建Syk亲和活性成分快速筛选方法；结合Syk酶-底物反应体系，筛选中药Syk活性抑制成分；并建立体内外炎症模型、哮喘气道炎症模型，采用分子生物学、免疫细胞共培养等技术，探讨中药Syk抑制成分抗气道炎症作用及其作用机制，阐释Syk信号通路与气道炎症的关系，为气道炎症防治提供新的思路和靶点，发现一类具有自主知识产权的中药Syk抑制剂候选物，为进一步的结构优化、分子设计奠定基础。

哮喘的发病机制复杂，而气道炎症是哮喘的病理基础，是哮喘症状反复发作的根本原因。因此，控制气道炎症是有效治疗哮喘的必要手段，是哮喘临床防治的原则之一。然而，迄今为止，仍没有理想的药物用于气道炎症的治疗，皮质激素等抗炎药在临床上仍存在较多的问题。而我国传统中药以其毒副作用小、良好的抗炎效果已被广泛应用于哮喘的临床治疗，但是，中药成分复杂多样，药效物质基础及其靶点机制仍不明确。因此，本项目基于炎症信号通路的关键调控分子-脾酪氨酸激酶（Syk），构建了Syk亲和活性成分快速筛选方法及Syk酶活性体外筛选方法，筛选Syk亲和抑制成分，并探讨其抗哮喘气道炎症作用及其作用机制。.本项目研究基于建立的Syk靶蛋白亲和成分筛选方法和Syk酶活性抑制筛选方法，从中药紫苏叶抗炎有效部位以及鸦胆苦醇衍生物等中筛选获得了数个Syk亲和成分和Syk酶活性抑制侯选成分。在此基础上，项目进一步证实中药紫苏叶有效位及其Syk亲和抑制主要成分、鸦胆苦醇衍生物具有显著的抗哮喘气道炎症作用，而且研究发现syk通路的抑制是其潜在的作用机制和靶点。.本项目研究结果有效阐释了Syk信号通路与气道炎症的关系，为气道炎症防治提供新的思路和靶点，而且项目研究发现一类具有自主知识产权的Syk抑制候选物，为进一步的结构优化、分子设计奠定基础。