Angiogenesis and Lymphangiogenesis in Airway Inflammatio

项目P-4将研究血管生成的机制、后果和可逆性： 慢性呼吸道炎症中的淋巴管生成。实验将探索改建的血管和淋巴管在粘膜肿胀和白细胞内流中的作用。将在可调控的转基因血管内皮生长因子过表达、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呼吸道疾病病理生理学的组成部分，因此提供了潜在的治疗靶点。目的#1重点研究呼吸道血管的生长、重塑和退化。我们的假设是，通过靶向血管的把关功能，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、细胞内流和气流力学的影响，以及(Iv)通过基因表达谱和体内噬菌体展示来识别新的血管靶点。目的#2阐述呼吸道炎症中淋巴管生成的细胞生物学。这个鲜有研究和了解的话题具有重要的相关性，因为粘膜淋巴管是清除渗出液和免疫细胞向淋巴结迁移的关键途径。令人信服的初步数据显示，在小鼠呼吸道中广泛的淋巴管生成后，肺分枝杆菌感染。我们的假设是淋巴管生成是呼吸道炎症的自然特征，任何损伤都可能加重粘膜水肿和气流阻塞。第一步将是确定正常呼吸道中的淋巴管和呼吸道炎症中的淋巴管生成的特征。然后将使用新的激动剂和拮抗剂来研究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。通过利用最近在阐明血管生成和淋巴管生成的分子基础方面的进展，这些研究有可能确定治疗炎症性呼吸道疾病的新方法。

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.