Epithelial-Mesenchymal Interactions in Pulmonary Fibrosis and Chronic Allograft Dysfunction (CLAD)

摘要 本申请是P01计划项目资助“宿主因子在调节炎症和炎症反应中的作用”的延续。 纤维增生性肺病”。这最初是由Paul Noble博士作为杜克的整体PI授予的 大学8/12最初的应用程序包括3个整体项目，项目1（P.诺贝尔博士），项目2（博士。 Jo Rae Wright，转移到巴里Stripp博士）和项目3（莫妮卡卡夫博士）。从2013年1月开始， 将Noble博士和Stripp博士的研究项目转移到CSMC后，我们开始与John博士合作 加州大学洛杉矶分校的贝尔佩里奥。本计划项目补助金申请的统一主题是， 肺上皮和下层间质决定了肺纤维化和肺纤维化患者体内平衡与疾病的关系 和CLAD。本申请的总体假设是IPF和CLAD均在 对上皮细胞功能障碍和祖细胞衰竭的反应。一个迷人的新兴生物学是 远端传导气道上皮和远端肺泡上皮之间的关系。是我们 CLAD的发展是由于远端气道祖细胞和IPF从远端气道祖细胞的传导失败， 肺泡上皮细胞衰竭然而，在一个隔室中祖细胞功能的丧失可能会很好地影响 另一个隔间。作为对上皮细胞稳态丧失的反应， 破坏性的间充质细胞群呈现出转移癌细胞的一些特征，即，的 侵入细胞外基质的能力。应用程序演变的最后一个原因是调查团队。 我们已经组建了一个研究团队，他们在肺部生物学方面产生了新的想法，开创了 合作实现最先进的工具，以解决这些新的想法，并在这两个方面都有成功的记录 机制动物研究以及利用人体组织样本，以促进我们对 IPF和CLAD的发病机制。在这个项目中，我们提出了一个纤维化的启动和持续的模型， 其源自传导气道上皮中的祖细胞功能障碍（多种祖细胞类型 在CLAD的情况下，肺泡上皮细胞（肺泡2型细胞-AT 2或AEC 2）在CLAD的情况下， IPF病例导致先天免疫细胞活化和间充质表型的募集， 破坏性和侵入性。我们已经确定了CLAD和IPF病理生物学的一些共同特征， 以及独特的方面。共同的主题包括招募侵袭性成纤维细胞表型， 通过侵袭细胞外基质的能力（项目1 - Noble）和p53与IL-22之间的相互作用来定义 在调节细支气管上皮细胞稳态（项目2 - Stripp和项目3 - Belperio）。

ABSTRACT This application is a renewal for the P01 Program Project Grant “Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease”. This was originally awarded with Dr. Paul Noble as the overall PI at Duke University in 8/12. The original application consisted of 3 overall projects, Project 1 (Dr. P. Noble), Project 2 (Dr. Jo Rae Wright, transferred to Dr. Barry Stripp), and Project 3 (Dr. Monica Kraft). Starting in January, 2013 upon moving Dr. Noble and Dr. Stripp’s research programs to CSMC, we initiated a collaboration with Dr. John Belperio at UCLA. The unifying theme of this Program Project Grant application is that crosstalk between the lung epithelium and underlying mesenchyme determines homeostasis versus disease in both pulmonary fibrosis and CLAD. The overarching hypothesis for this application is that both IPF and CLAD develop in response to epithelial cell dysfunction AND progenitor cell failure. A fascinating emerging biology is the relationship between the distal conducting airway epithelium and the distal alveolar epithelium. It is our contention that CLAD develops from a failure of conducting distal airway progenitor cells and IPF from distal alveolar epithelial cell failure. However, the loss of progenitor cell function in one compartment may well influence the other compartment. In response to the loss of epithelial cell homeostasis, there is activation and recruitment of a destructive mesenchymal cell population that takes on some features of metastasizing cancer cells, i.e., the ability to invade extracellular matrix. The final reason for the evolution in the application is the investigative team. We have assembled a team of investigators that have generated new ideas in lung biology, pioneered and partnered to achieve state of the art tools to address these new ideas and have a track record of success in both mechanistic animal studies as well as utilizing human tissue samples to advance our understanding of the pathogenesis of IPF and CLAD. In this Program, we propose a model for the initiation and perpetuation of fibrosis that emanates from progenitor cell dysfunction in the conducting airway epithelium (multiple progenitor cell types including club cells) in the case of CLAD, and the alveolar epithelium (alveolar type 2 cell- AT2 or AEC2) in the case of IPF leading to innate immune cell activation and the recruitment of a mesenchymal phenotype that is destructive and invasive. We have identified some common features in the pathobiology of CLAD and IPF as well as unique aspects. The common themes include the recruitment of an invasive fibroblast phenotype as defined by the ability to invade extracellular matrix (Project 1 – Noble) and the interplay between p53 and IL-22 in regulating bronchiolar epithelial homeostasis (Project 2 – Stripp and Project 3 – Belperio).