The Pulmonary Lymphatics in Inflammation and Disease

炎症和疾病中的肺淋巴管

• 批准号: 9981809
• 负责人: Hasina Outtz Reed
• 金额: $ 17.19万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-23 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981809
• 关键词: Address; Adoptive Transfer; Adult; Affect; Alveolar; American; Asthma; Autoantibodies; Biology; Blood; Blood Platelets; Blood Vessels; Blood flow; C-Type Lectins; Cause of Death; Cell Death; Cell Surface Receptors; Cells; Chronic lung disease; Cigarette; Communities; Development; Development Plans; Diagnostic radiologic examination; Diphtheria Toxin; Disease; Edema; Environment; Enzyme-Linked Immunosorbent Assay; Exposure to; Fibrosis; Flow Cytometry; Functional disorder; Genetic; Graft Rejection; Histologic; Human; Immune; Immunity; Immunohistochemistry; Impairment; Inflammation; Inflammation Mediators; Inflammatory Infiltrate; Label; Lectin; Leukocyte Trafficking; Leukocytes; Link; Liquid substance; Lung; Lung Transplantation; Lung diseases; Lymphatic; Lymphatic Abnormalities; Lymphatic Endothelial Cells; Lymphatic System; Lymphoid Cell; Lymphoid Tissue; Matrix Metalloproteinases; Mediating; Mentorship; Modeling; Molecular Analysis; Mus; Mutant Strains Mice; Pathogenesis; Pathogenicity; Patients; Pennsylvania; Pharmacology; Phenotype; Physiological; Play; Process; Production; Pulmonary Edema; Pulmonary Emphysema; Pulmonary Fibrosis; Pulmonary function tests; Research Personnel; Resources; Respiratory physiology; Role; Severity of illness; Structure of parenchyma of lung; Testing; Training; Transplantation; United States; Universities; Venous; X-Ray Computed Tomography; base; career development; cell motility; cell type; cytokine; density; diphtheria toxin receptor; draining lymph node; human disease; human model; immunoregulation; improved; in vivo Model; inflammatory milieu; lung injury; lymph flow; lymph nodes; lymphatic drainage; lymphatic vessel; migration; mouse model; new therapeutic target; novel; pathogen; postnatal; prevent; receptor; tertiary lymphoid organ; therapeutic target; trafficking; transcriptome sequencing; transcriptomics

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.

项目概要/摘要 由于肺部容易受到外界环境的影响，肺淋巴管被认为对肺功能至关重要。 水肿和持续接触病原体。事实上，肺淋巴管异常可见于 与几乎所有慢性肺部疾病有关，包括移植排斥、肺纤维化和 肺气肿影响了近 3200 万美国人。然而，目前尚不清楚这些是否 淋巴管异常是疾病的结果，或者如果淋巴功能障碍是致病性的， 尚未探索的潜在治疗靶点。该提案解决了我们学习能力方面的突出差距 肺淋巴功能，并使用两种新颖的方法研究淋巴管在肺部疾病中的基本作用 肺淋巴流动受损的小鼠模型。第一个模型使用 Clec2 突变小鼠，该小鼠具有 由于淋巴-静脉交界处缺少血小板栓塞和逆流，淋巴液流动严重受损 血液进入淋巴系统，阻止淋巴引流。在第二个模型中，肺特异性淋巴管 通过诱导白喉毒素介导的小鼠肺淋巴内皮细胞细胞死亡来实现缺失 移植。这些模型表明，淋巴功能障碍导致白细胞积聚并形成 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，两种模型都将是 用于研究肺淋巴管在白细胞运输中的作用并测试淋巴功能是否正常 在免疫细胞规范和肺部炎症环境中发挥作用。目标 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淋巴功能障碍的假设 小鼠自发性肺气肿表型，并将研究淋巴功能障碍的机制 通过救援研究导致肺损伤。预计这些研究将为理解提供体内模型 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到的作用 用于肺气肿的淋巴管。该提案还在职业发展计划中发挥着核心作用，以成为 一位成功的独立研究者，专注于血管生物学和疾病。此处描述的培训计划 提供获得人类疾病小鼠模型、转录组学和生理学方面的专业知识的机会 以及小鼠肺部的放射线分析。宾夕法尼亚大学是一个理想的环境 执行这个训练计划不仅因为其优秀的体能资源，还因为其智力资源 由对早期研究人员提供强有力指导的研究人员组成的社区。