MALT1调控过敏性哮喘发生的机制研究

Asthma is one of the severe diseases which affect human health at present. Theprocess of asthma induction is complicated. It has been known that immune system play an important role in regulating allergic asthma response, especially T cells, eosinophils and mast cells, but the mechanism is still remaining unclear. Under physiological conditions, MALT1 together with BCL10 and CARMA1 to form a complex, CBM, which play an important role in regulating the differentiation and function of T cells. Our preliminary data showed that: MALT1-/- mice showed no typical asthma response, with much less eosinophil recruitment and Th2 cytokine production. In this project, we are planning to further investigate the mechanism of how MALT1 regulate the induction of asthma response by its protease activity. Based on these data, our scientific questions are: 1,Does MALT1 regulate the induction of allergic asthma? What’s the mechanism? 2,Does MALT1 regulate the differentiation and function of T cells and regulate the induction of allergic asthma by its protease activity? What’s the mechanism? 3,Does the protease activity of MALT1 in immune cells from the BALF increased or not? To define the mechanism of how MALT1 regulate the differentiation and function of T cells and how MALT1 regulate the induction of allergic asthma response by its protease activity, will shed light on the biological process of the induction of allergic asthma, and provide the theoretical support and new orientation for the development of new drugs for therapy of allergic asthma, which is one of the severe diseases affecting human health.

哮喘病是当今社会影响人类健康的一种重要疾病，病因复杂。已知免疫系统对过敏性哮喘的发生具有重要的调节作用，特别是T细胞、嗜酸性粒细胞和肥大细胞，但其机制仍然不很清楚。MALT1在生理条件下与BCL10和CARMA1共同组成CBM复合体，该复合体对T细胞的功能分化具有重要调节作用。我们前期工作表明：敲除MALT1的小鼠不能诱导出典型的哮喘反应，嗜酸性粒细胞的募集和Th2细胞因子的产生都显著降低。本项目拟深入研究MALT1蛋白酶活性对哮喘发生的调控机理。我们的科学问题是：1，MALT1蛋白酶活性对T细胞功能分化及过敏性哮喘的发生是否有调控作用？其机制是什么？2，哮喘病患者的PBMC、肺分泌液样本中免疫细胞的MALT1蛋白酶活性是否升高？阐明MALT1蛋白酶活性对T细胞功能分化及过敏性哮喘反应诱导的作用，有助深入认识过敏性哮喘的发病机制，为研发治疗过敏性哮喘的新药提供理论基础和方向。

随着过敏性鼻炎及哮喘发病率的提高,过敏性疾病已成为当今社会一个重要的健康问题。目前的治疗药物针对性差，效果不理想。MALT1对免疫细胞的功能具有重要的调节作用。因此，本项目旨在研究MALT1对过敏性哮喘发生发展的影响及其作用机制。我们的结果表明：缺失MALT1，在小鼠模型中就诱导不出典型的过敏性哮喘反应。MALT1对Th2型T细胞的分裂分化具有重要的调控作用；MALT1影响T细胞和嗜酸性粒细胞在肺部的募集和浸润；MALT1影响肥大细胞的脱颗粒过程以及炎症因子的释放。MALT1功能的实施是通过其酶活性来实现的。通过筛选MALT1抑制剂可为治疗哮喘病药物的研发提供新的解决方案。在本基金的支持下，我们还开展了如下研究：1，MALT1通过调节GLS1介导的谷氨酰胺代谢影响银屑病的发生发展。2，IDO抑制剂和Vg9Vd2 T细胞共同应用对三阴性乳腺癌具有显著疗效。3，内分泌干扰化学品（EDC）和新烟碱类杀虫剂（NEO）在人体内的残留以及对健康的影响等。