Role of Angiogenesis in IBD Pathogenesis

血管生成在 IBD 发病机制中的作用

• 批准号: 6965430
• 负责人: CLAUDIO FIOCCHI
• 金额: $ 32.45万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6965430
• 关键词: angiogenesis; angiogenesis factor; angiogenesis inhibitors; clinical research; cytokine; disease /disorder etiology; disease /disorder model; extracellular matrix; extracellular matrix proteins; growth factor; human subject; inflammatory bowel diseases; integrins; intestinal mucosa; laboratory mouse; leukocytes; pathologic process; patient oriented research; vascular endothelium

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.

描述（由申请人提供）：炎症性肠病（IBD）涉及多种生物因素的相互作用，其中非免疫细胞代表了疾病发生过程中被低估但至关重要的组成部分。尤其;粘膜内皮细胞通过血管生成在慢性炎症中发挥关键作用，血管生成是一种由多种细胞类型和多种可溶介质协调参与介导的复杂过程，可分为四大类：a）生长因子，直接促进内皮细胞增殖和迁移，b) 整合素、允许内皮细胞与其他细胞和细胞外基质 (ECM) 通讯的粘附分子，c) 白细胞、细胞因子和趋化因子，驱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塑。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，为支持血管生成这一概念提供了坚实的证据。在肠道炎症的发生和持续过程中起着至关重要的作用。该提案将通过测试以下中心假设来研究 IBD 血管生成的机制：血管生成是 IBD 的关键组成部分，并有助于疾病发病机制。这一假设将通过四个具体目标进行检验：1）获得 IBD 粘膜血管化和内皮细胞活化增加的证据； 2) 定义IBD中产生的主要血管生成因子、其来源和生物活性； 3) 表征 ECM 中内皮细胞介导的促进血管生成的变化； 4) 研究抗血管生成化合物在 IBD 动物模型中的治疗效果。正如对患有肿瘤、自身免疫和炎症性疾病的人类和动物的临床试验所表明的那样，阻断血管生成可能会中断 IBD 中发生的免疫-非免疫细胞相互作用的慢性周期，并导致临床改善。