Angiogenesis and Lymphangiogenesis in Airway Inflammatio

气道炎症中的血管生成和淋巴管生成

• 批准号: 6955252
• 负责人: Donald M McDonald
• 金额: $ 44.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6955252
• 关键词: Mycoplasma; angiogenesis; bacterial cytopathogenic effect; biological signal transduction; blood vessels; bone marrow transplantation; gene expression; growth factor receptors; immunocytochemistry; inflammation; integrins; laboratory mouse; leukocytes; lung lavage; lymphatic system; phage display; receptor expression; respiratory epithelium; respiratory function; respiratory infections; transmission electron microscopy; vascular endothelial growth factors

Project P-4 will examine mechanisms, consequences, and reversibility of angiogenesis: lymphangiogenesis in chronic airway inflammation. Experiments will explore the role of remodeled blood vessels and lymphatic vessels in mucosal swelling and leukocyte influx. Cellular mechanisms will be studied in mouse models of regulated transgenic overexpression of VEGF, Mycoplasma pulmonis infection, and growth factor stimulation and inhibition. The overall concept is that angiogenesis and lymphangiogenesis are integral to the pathophysiology of inflammatory airway disease and thus provide potential therapeutic targets. Aim #1 focuses on the growth, remodeling, and regression of airway blood vessels. Our hypothesis here is that by targeting the gatekeeper function of blood vessels, reversal of angiogenesis would reduce mucosal edema and leukocyte influx. We will (i) identify sensitive readouts of vascular regression, (ii) explore strategies of reversing angiogenesis, (iii) determine the effects of reversal on blood vessel leakiness, cell influx, and airflow mechanics, and (iv) identify new vascular targets by gene expression profiling and in vivo phage display. Aim #2 addresses the cell biology of lymphangiogenesis in airway inflammation. This little studied and poorly understood topic has important relevance because mucosal lymphatics are key routes for clearance of extravasated fluid and migration of immune cells to lymph nodes. Compelling preliminary data show extensive lymphangiogenesis in mouse airways after M. pulmonis infection. Our hypothesis is that lymphangiogenesis is a natural feature of airway inflammation, and any impairment could exaggerate mucosal edema and airflow obstruction. The first step will be to characterize the lymphatics in normal airways and lymphangiogenesis in airway inflammation. The role of VEGFR-3 signaling in lymphangiogenesis will then be examined using novel agonists and antagonists. Subsequent experiments will determine whether impaired lymphatic drainage leads to bronchial lymphedema. By taking advantage of recent progress in elucidating the molecular basis of angiogenesis and lymphangiogenesis, these studies have the potential of identifying new approaches for treating inflammatory airway disease.

P-4 项目将研究血管生成的机制、后果和可逆性： 慢性气道炎症中的淋巴管生成。实验将探讨重塑的血管和淋巴管在粘膜肿胀和白细胞流入中的作用。将在 VEGF 转基因过度表达、肺支原体感染以及生长因子刺激和抑制的小鼠模型中研究细胞机制。总体概念是血管生成和淋巴管生成是炎症性气道疾病病理生理学不可或缺的一部分，因此提供了潜在的治疗靶点。目标#1 关注气道血管的生长、重塑和消退。我们的假设是，通过针对血管的看门人功能，血管生成的逆转将减少粘膜水肿和白细胞流入。我们将（i）识别血管退化的敏感读数，（ii）探索逆转血管生成的策略，（iii）确定逆转对血管渗漏、细胞流入和气流力学的影响，以及（iv）通过基因表达谱和体内噬菌体展示识别新的血管靶标。目标#2 解决气道炎症中淋巴管生成的细胞生物学问题。这个研究很少且了解甚少的主题具有重要的相关性，因为粘膜淋巴管是清除外渗液体和免疫细胞迁移到淋巴结的关键途径。令人信服的初步数据显示，肺分枝杆菌感染后，小鼠气道中存在广泛的淋巴管生成。我们的假设是，淋巴管生成是气道炎症的自然特征，任何损伤都可能加剧粘膜水肿和气流阻塞。第一步是描述正常气道中的淋巴管和气道炎症中的淋巴管生成。然后将使用新型激动剂和拮抗剂检查 VEGFR-3 信号在淋巴管生成中的作用。随后的实验将确定淋巴引流受损是否会导致支气管淋巴水肿。通过利用阐明血管生成和淋巴管生成的分子基础的最新进展，这些研究有可能确定治疗炎症性气道疾病的新方法。