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

肺纤维化和慢性同种异体移植物功能障碍 (CLAD) 中的上皮-间质相互作用

基本信息

批准号：
10197999
负责人：
Paul Wesley Noble
金额：
$ 236.83万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197999
关键词：
AGTR2 gene Achievement Address Adhesives Allografting Alveolar Animal Model Animals Applications Grants Automobile Driving Award Basal Cell Biochemical Biology Bronchoalveolar Lavage Bronchoscopy Cells Chronic Clinical Trials Collaborations Defect Disease Distal Epithelial Epithelial Cells Evolution Extracellular Matrix Failure Fibroblasts Fibrosis Functional disorder Future Homeostasis Human Immune Immune checkpoint inhibitor Immunization Immunofluorescence Immunologic Immunohistochemistry Inflammatory Injury Integration Host Factors Invaded Ligands Lung Lung diseases Mediating Medical Mesenchymal Mesenchyme Modeling Neoplasm Metastasis PTK2 gene Pathogenesis Pathway interactions Patients Phenotype Population Process Production Program Research Project Grants Pulmonary Fibrosis Regulation Research Research Personnel Reserve Cell Role Sampling TP53 gene Testing Tissue Sample Tissues Universities airway epithelium alveolar epithelium cancer cell cell type epithelial repair epithelial stem cell fascinate human tissue immune activation immunoregulation insight interleukin-22 mouse model novel programs recruit repaired response rho stem cell function stem cells success therapy development tool transcriptome

项目摘要

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).

抽象的该申请是P01计划项目的续签，授予“调节炎症和纤维增生性肺部病”。这最初是由保罗·诺布尔（Paul Noble）博士授予的，作为杜克大学的整体PI 8/12大学。最初的应用程序包括3个整体项目，项目1（P. Noble博士），项目2（博士乔·雷·赖特（Jo Rae Wright）转移到巴里·斯特里普（Barry Stripp）博士和第3项目（莫妮卡·卡夫（Monica Kraft）博士）。从2013年1月开始将Noble博士和Stripp博士的研究计划移至CSMC，我们与John博士启动了合作贝尔珀里奥在加州大学洛杉矶分校。该计划项目授予应用程序的统一主题是肺上皮和基础间质决定了两种肺纤维化的稳态与疾病和外壳。此应用程序的总体假设是IPF和clad在对上皮细胞功能障碍和祖细胞衰竭的反应。令人着迷的新兴生物学是远端导电通道上皮与远端肺泡上皮之间的关系。这是我们的斗争的争论是由于传导远端气道祖细胞和IPF而产生的。肺泡上皮细胞衰竭。但是，一个隔室中祖细胞功能的丧失可能会影响另一个隔间。响应上皮细胞稳态的丧失，存在激活和募集具有转移癌细胞的某些特征的破坏性间充质细胞群能够入侵细胞外基质。应用程序演变的最终原因是调查团队。我们组建了一个研究人员团队，这些研究人员在肺部生物学上产生了新想法，开创性和合作以实现最先进的工具来解决这些新想法，并在两者中取得成功的记录机械动物研究以及使用人体组织样本来促进我们对 IPF和clad的发病机理。在此程序中，我们提出了一个模型，用于纤维化的主动性和永久性从传导气道上皮中的祖细胞功能障碍发出（多个祖细胞类型在外壳的情况下）和肺泡上皮（肺泡2型细胞AT2或AEC2） IPF的病例导致先天免疫细胞激活和募集间充质表型破坏性和侵入性。我们已经确定了clad和ipf病理生物学中的一些共同特征以及独特的方面。常见的主题包括招募侵入性成纤维细胞表型由入侵细胞外基质（项目1 - 贵族）和p53和IL-22之间的相互作用的能力定义在调节支气管上皮稳态时（项目2 - Stripp和Project 3 - Belperio）。