The Pulmonary Lymphatics in Inflammation and Disease

项目摘要/摘要 肺淋巴管被认为是肺功能的关键，因为肺容易受到 浮肿和他们不断接触病原体。事实上，异常的肺淋巴管可见于 几乎与每种慢性肺部疾病有关，包括移植排斥反应、肺纤维化和 肺气肿，这两种疾病加起来影响了近3200万美国人。然而，目前还不清楚这些是否 淋巴管异常是疾病的结果，或者如果淋巴功能障碍是致病的，留下 潜在的治疗靶点尚未开发。这项建议既解决了我们在学习能力上的一个突出差距 肺淋巴功能，也研究了淋巴管在肺部疾病中的基础作用 肺淋巴流受损的小鼠模型。第一个模型使用的是Clec2突变小鼠，这些小鼠有 由于淋巴-静脉交界处没有血小板堵塞和逆行血流，导致淋巴流动严重受损 血液进入淋巴系统，阻止淋巴引流。在第二个模型中，肺特异性淋巴 白喉毒素诱导小鼠肺淋巴管内皮细胞死亡实现缺失 移植。这些模型表明淋巴功能障碍会导致白细胞的聚集和形成。 肺实质中的淋巴组织。值得注意的是，淋巴流动受损的小鼠也有肺泡 类似于人类肺气肿的肿大和肺损伤。在本提案的目标1中，这两种模式都将 用于研究肺淋巴管在白细胞转运中的作用，并测试淋巴功能 在免疫细胞规格和肺部炎症环境中发挥作用。AIM 2将使用肺 功能测试、CT成像和表达研究，以检验淋巴功能障碍导致 小鼠的自发性肺气肿表型，并将探讨淋巴功能障碍的机制 使用救援性研究导致肺损伤。这些研究预计将提供活体模型来了解 淋巴功能、炎症和肺损伤之间的相互作用，可能会揭示一个未被认识的作用 用于肺气肿的淋巴管。这一提议也在职业发展计划中发挥着核心作用 一位成功的独立研究员，专注于血管生物学和疾病。这里描述的培训计划 提供了获得人类疾病的小鼠模型、转录组学和生理学方面的专业知识的机会 以及对小鼠肺的放射学分析。宾夕法尼亚大学是一个理想的环境， 执行这个培训计划，不仅是因为它优越的体力资源，也是因为它的智力 研究人员社区，对早期调查人员有很强的指导作用。

PROJECT SUMMARY/ABSTRACT Pulmonary lymphatic vessels are thought to be critical for lung function due to the vulnerability of the lungs to edema and their constant exposure to pathogens. Indeed, abnormal pulmonary lymphatics are seen in association with nearly every chronic lung disease including transplant rejection, pulmonary fibrosis, and emphysema, which combined affect nearly 32 million Americans. However, it remains unclear whether these abnormal lymphatics are a consequence of the disease or if lymphatic dysfunction is pathogenic, leaving potential therapeutic targets unexplored. This proposal addresses both an outstanding gap in our ability to study pulmonary lymphatic function and also investigates the basic role of lymphatics in lung disease using two novel mouse models of impaired pulmonary lymphatic flow. The first model uses Clec2-­mutant mice, which have severely impaired lymph flow due to an absent platelet plug at the lympho-­venous junction and retrograde flow of blood into the lymphatic system that prevents lymphatic drainage. In the second model, lung-­specific lymphatic deletion is achieved by inducing diphtheria toxin-­mediated cell death of lymphatic endothelial cells in mouse lung transplants. These models show that lymphatic dysfunction leads to accumulation of leukocytes and formation of lymphoid tissue in the lung parenchyma. Significantly, mice with impaired lymphatic flow also have alveolar enlargement and lung injury that resembles human emphysema. In Aim 1 of this proposal, both models will be used to investigate the role of pulmonary lymphatics in leukocyte trafficking and test whether lymphatic function plays a role in immune cell specification and the inflammatory milieu of the lung. Aim 2 will use pulmonary function tests, CT imaging, and expression studies to test the hypothesis that lymphatic dysfunction causes a spontaneous emphysema phenotype in mice, and will investigate the mechanism by which lymphatic dysfunction causes lung injury using rescue studies. These studies are predicted to provide in vivo models for understanding the interplay between lymphatic function, inflammation, and lung injury and may uncover an unappreciated role for lymphatics in emphysema. This proposal also plays a central role in a career development plan for becoming a successful independent investigator focused on vascular biology and disease. The training plan described here provides an opportunity to gain expertise in mouse modeling of human disease, transcriptomics, and physiologic and radiographic analysis of the mouse lung. The University of Pennsylvania is an ideal environment in which to execute this training plan not only because of its excellent physical resources, but also because of its intellectual community of researchers with a track record of strong mentorship of early stage investigators.