TIM-1-TIM-4信号通路在支气管哮喘中的作用及其分子机制

Bronchial asthma (also called asthma) is a chronic airway inflammatory disease，which is a serious danger to public health. The exact mechanism by which asthma develops has not yet been fully elucidated. The co-stimulators TIM-1/TIM-4 and theirs TIM-1-TIM-4 pathway were involved in the activation of T cells and the differentiation of Th1, Th2, Th17 and Treg cells, but the molecular mechanism of their action remains unknown. The aim of this study is to construct the eukaryotic expression vectors of human TIM-1-Fc and TIM-4-Fc, respectively. The human TIM-1-Fc and TIM-4-Fc fusion proteins were highly expressed in mammalian cells and purified by affinity chromatography. On this basis, we investigated the biological activity of human TIM-1-Fc and TIM-4-Fc in vitro and in vivo. Then we respectively evaluated the effect of TIM-1-Fc and TIM-4-Fc on the inflammation in a murine asthma model，through which to explore the role of the TIM-1-TIM-4 pathway in T-cell responses and asthma. This study will provide new ideas and targets for the prevention and treatment of bronchial asthma.

支气管哮喘（简称哮喘）是一种严重危害公众健康的气道慢性反应性炎症性疾病，确切机制尚未阐明。共刺激分子TIM-1与TIM-4及其TIM-1-TIM-4通路参与T细胞活化，Th细胞亚群(Th1、Th2、Th17和Treg)的分化调节，但具体机制不清楚。本课题拟分别构建人TIM-1-Fc和TIM-4-Fc真核表达载体，在哺乳动物细胞中实现TIM-1-Fc和TIM-4-Fc融合蛋白高效表达，并通过亲和层析技术纯化重组蛋白。在此基础上，分别对TIM-1-Fc和TIM-4-Fc体内外生物学功能的进行研究。探讨TIM-1-Fc和TIM-4-Fc阻断共刺激通路对哮喘炎症的影响，以阐释TIM-1-TIM-4通路对T细胞应答和哮喘的作用。此研究将为支气管哮喘的防治提供新思路和新靶点。

本课题分别构建人TIM-1-Fc 和TIM-4-Fc 真核表达载体，在哺乳动物细胞中实现TIM-1-Fc 和TIM-4-Fc 融合蛋白高效表达，并通过亲和层析技术纯化重组蛋白。通过体内外实验，靶向调控TIM-1-TIM-4信号途径。我们发现哮喘存在Th1/Th2 和 Th17/Treg失衡，通过TIM-1-Fc 和TIM-4-Fc 可以调控哮喘免疫失衡。此研究为支气管哮喘的防治提供新思路和新靶点。