Angiogenesis and Lymphangiogenesis in Airway Inflammatio

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、肺支原体感染和生长因子刺激和抑制的受调节转基因过表达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性气道疾病的病理生理学的组成部分，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，通过靶向血管的看门人功能，逆转血管生成将减少粘膜水肿和白细胞流入。我们将（i）确定血管消退的敏感读数，（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确定新的血管靶点。目的#2解决了气道炎症中淋巴管生成的细胞生物学。这一研究较少且理解不深的主题具有重要的相关性，因为粘膜炎症是清除渗出液和免疫细胞迁移至淋巴结的关键途径。令人信服的初步数据显示，小鼠气道中广泛的淋巴管生成后，M。肺部感染我们的假设是，淋巴管生成是气道炎症的一个自然特征，任何损伤都可能加重粘膜水肿和气流阻塞。第一步将是表征正常气道中的炎症和气道炎症中的淋巴管生成。然后将使用新的激动剂和拮抗剂来检查VEGFR-3信号传导在淋巴管生成中的作用。随后的实验将确定受损的淋巴引流是否会导致支气管水肿。通过利用最新的进展，阐明血管生成和淋巴管生成的分子基础，这些研究有可能确定新的方法来治疗炎症性气道疾病。

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.