Role of Angiogenesis in IBD Pathogenesis

描述(申请人提供)：炎症性肠病(IBD)涉及多种生物因素的相互作用，其中非免疫细胞是疾病肥厚形成的一个被低估但关键的组成部分。特别是，粘膜内皮细胞通过血管生成在慢性炎症中发挥关键作用，这是一个由多种细胞类型和各种可溶性介质协调参与的复杂过程，可分为四大类：a)生长因子，直接促进内皮细胞的增殖和迁移；b)整合素，黏附分子，允许内皮细胞与其他细胞和细胞外基质(ECM)进行沟通；c)白细胞，细胞因子和趋化因子，推动免疫介导的内皮细胞激活；d)蛋白水解酶和ECM蛋白，负责新血管形成所需的组织重建。关于血管生成在癌症、自身免疫和慢性炎症中的作用的最新知识，以及我们自己通过研究IBD患者和实验性结肠炎小鼠的组织和细胞获得的初步数据，提供了坚实的证据，支持血管生成在肠道炎症的启动和持续中发挥重要作用的概念。这项建议将通过检验以下中心假设来研究IBD中血管生成的机制：血管生成是IBD的关键组成部分，并有助于疾病的发病机制。这一假说将通过四个具体目标得到验证：1)获得IBD黏膜中血管形成和内皮细胞激活增加的证据；2)确定在IBD中产生的主要血管生成因子、它们的来源和生物学活性；3)表征内皮细胞介导的促进血管生成的ECM的变化；4)研究抗血管生成化合物在IBD动物模型中的治疗作用。阻断血管生成可能会中断IBD发生的免疫-非免疫细胞相互作用的慢性循环，并导致临床改善，这是在患有肿瘤、自身免疫和炎症性疾病的人类和动物的临床试验中所表明的。

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) involves the interplay of multiple biological factors, among which nonimmune cells represent an underrated but crucial component of disease pachogenesis. In particular; mucosal endothelial cells play a key role in chronic inflammation through angiogenesis, a complex process mediated by the coordinated involvement of multiple cells types and a variety of sol nble mediators, which can be grouped into four major categories: a) growth factors, that directly promote endothelial cell proliferation and migration, b) integrins, adhesion molecules that allow communication of endothelial cells with other cells and the extracellular matrix (ECM), c) leukocytes, cytokines and chemokines, that drive immune-mediated endothelial cell activation, and d) proteolytic enzymes and ECM proteins, that are responsible for the tissue remodeling necessary to formation of new vessels. Sate-of-the-art knowledge on tie role of angiogenesis in cancer, autoimmunity and chronic inflammation, and our own preliminary data, obtained by studying tissues and cells from IBD patients and mice with experimental colitis, provide solid evidence supporting the concept that angiogenesis plays a vital role in initiation and perpetuation of intestinal inflammation. This proposal will investigate mechanisms of angiogenesis in IBD by testing the following central hypothesis: Angiogenesis is a critical component of IBD and contributes to disease pathogenesis. This hypothesis will be tested by four specific aims: 1) Obtain evidence of increased vascularization and endothelial cell activation in IBD mucosa; 2) Define the dominant angiogenic factors produced in IBD, their origin, and biological activity; 3) Characterize endothelial cell-mediated changes in the ECM that promote angiogenesis; 4) Investigate the therapeutic effects of anti-angiogenic compounds in animal models of IBD. Blocking angiogenesis may interrupt the chronic cycle of immune-nonimmune cell interactions occurring in IBD and result in clinical improvement, as suggested by clinical trials in humans and animals suffering from neoplastic, autoimmune and inflammatory disorders.