Immune regulation of angiogenesis in inflammatory bowel diseases

炎症性肠病(IBD)具有两个重要的细胞生物学特征，即T细胞活化和血管生成。在这个框架中，干扰素-γ被认为是免疫功能和T细胞激活的重要调节分子。血管内皮生长因子被认为是一种主要的血管生成因子。在本课题组前期研究成果的基础上，本项目重点研究了这两个主要致病因子在IBD发病中的两个新的互补作用，即血管内皮生长因子对T细胞活化的调节和干扰素-γ作为血管生成抑制因子的活性。T细胞导向法的具体目标是：(1)评估结肠炎T细胞上血管内皮生长因子受体KDR的功能作用；(2)分析KDR和神经毛刺素-1在T细胞中的联合作用；(3)证明T细胞中KDR的表达与人IBD发病机制的相关性。该项目的血管分支将旨在剖析干扰素-γ和血管内皮生长因子对(4)小鼠扩张性结肠炎模型的血管功能和(5)从人类炎症性肠病组织分离的血管内皮细胞的分子水平的联合作用。开发IBD综合治疗的新策略是本项目的共同目标。

Inflammatory bowel diseases (IBD) are characterized by two important cell biological features, namely T-cell activation and angiogenesis. In this framework Interferon (IFN)-y is regarded as an important regulatory molecule of immune function and T-cell activation. Vascular endothelial growth factor is known as a major angiogenesis factor. Based on previous results of our group, the project focuses on two new and complementary functions of both of these major pathogenesis factors in IBD, namely the regulation of T-cell activation by VEGF and the activity of IFN-y as an inhibitor of angiogenesis. Specific goals of the T-cell directed approach are (1) to evaluate the functional role of the VEGF receptor KDR on T-cells in colitis, (2) to analyze combination effects of KDR and neuropilin-1 in Tcells and (3) to prove the relevance of KDR-expression in T-cells for pathogenesis of human IBD. The vascular branch of the project will target to dissect the combination effects of IFN-y and VEGF on (4) blood vessel function in expenmental colitis models in mice and (5) at the molecular level in blood vessel endothelial cells isolated from inflammatory bowel disease tissues of humans. It is the common goal of this project to exploit the obtained results for the development of new strategies for combination therapy of IBD.