具有免疫调控作用的新共生菌产物研究

Innate immunity plays an important role in the body against foreign pathogens, study of the important pathway and receptor in the innate immunity will bring new hope for the control of a series of major high refractory disease (such as virus infection, tumor, autoimmune disease). Toll like receptors and inflammasome are important receptor molecules that develpop an effects in the process of host resistance to infection. In the past ten years, from the point of application on the phenomenon of "symbiosis" and "immune compromise" between host and fungus, the claimer discovered a series of new immunosuppressive molecules from a variety of host materials using advanced technology and method .This project aims to: (1) study on the mechanisms of regulation of new framework of dalesconol A and B on TLR pathway and inflammatory corpuscle by chemical modification and molecular biology technology; (2) continue to acquire symbionts and quickly found the immune regulation molecules from other the host material, and then studies the characteristics and mechanism of regulation using the platform and the existing methods of science system . The project is expected not only to find new probe molecules that selectively effects on the TLR and related pathway, new pathways and new targets, but also to find new leading compounds of immunomodulatory drugs, and the nature and law of "immune compromise" to promote the development of related disciplines.

天然免疫在机体抵抗外来病原体方面起着重要作用，深入研究天然免疫中的重要通路、受体等可为一系列重大高发难治之症（如病毒感染、肿瘤、自身免疫性疾病）的控制带来新希望。Toll 样受体和炎性小体都是参与天然免疫的重要受体分子，在宿主抗感染过程中发挥作用。近十年来，申请者重点从宿主与共生菌之间的“互惠共生”和“免疫妥协”现象入手，采用多学科先进技术与方法，从多种宿主材料中分离共生菌，并发现了一系的新免疫抑制分子。本项目拟：（1）集成化学修饰、分子生物学等技术，深入研究新骨架分子 dalesconol A 和 B 等对 TLR通路及炎性小体的调控机制；（2）利用已有的平台和方法学体系继续从其它宿主材料中获取共生菌并快速发现其产生的免疫调控新分子，继而深入研究其调控特点与机制。本项目既有望发现选择性作用于 TLR 及有关通路的新探针分子及相关的新通路、新靶点，又有望发现新免疫调节药物的先导化合物。

Toll样受体（Toll-like receptors，TLRs）及其通路调控与高发难治之症（如病毒感染、肿瘤、红斑狼疮等自身免疫疾病）有密切关系，本项目围绕具有免疫调控作用的新共生菌产物这一研究目标，在新活性天然分子的发现、作用机制及其合成生物学研究面均取得了重要研究进展。在Organic Letters、Scientific Reports等期刊发表论文6篇，申请专利1项。具体取得了以下进展：1）通过突变生物合成，从真菌Daldinia eschscholzii的发酵液中得到一系列结构新颖的萘酚二聚体，个别化合物具有Toll-like receptor 5抑制活性；2）通过定向生物合成，成功诱导初出具有TLR4抑制活性的吲哚生物碱；3）分离到一系列具有抗菌、抗癌等生物活性的天然活性物质。这些发现为进一步发现调控Toll样受体的新通路及新靶点奠定了基础。