Molecular Regulation of Progressive Pulmonary Fibrosis

摘要 我们的实验室一直致力于阐明调控进展的分子机制。 肺纤维化已有二十多年。我在特发性肺纤维化研究领域的贡献 包括使用基质透明质酸作为模型分子来剖析进展性肺的分子机制 纤维化症。我们已经确定了透明质酸片段在调节肺部炎症中的作用。我们发现 透明质酸和透明质酸受体在肺部炎症和肺干细胞再生中起作用。 我们在小鼠和特发性肺纤维化外植体中发现了侵袭性成纤维细胞表型。 我们通常被认为是扩展了矩阵不仅仅是粘合剂并且具有动态作用的概念 在调节肺部生物学方面。我们工作的一个方面让我感到自豪，那就是我们发表了许多 我们的理科在非专业期刊上有合理的影响。这表明虽然我们研究的是肺， 我们提出的概念被认为是更广泛的受众感兴趣的。这款R35的目标 应用是确定导致持续性纤维化的上皮-间充质相互作用。具体来说， 我们建议在本R35中确定AEC2在小鼠和人的再生能力失败的机制，以 确定AEC2更新能力受损小鼠间充质扩张的机制，以确定 β-arrestin1和CD44调节侵袭性成纤维细胞表型的机制及鉴定 侵袭性成纤维细胞损害AEC2细胞更新的机制。增加科学知识 了解这些相互作用在肺纤维化中的潜在机制和作用模式 显著帮助进行性肺纤维化患者的治疗发展。我的信念是我们 需要一种促进肺泡祖细胞更新的药物和一种针对致病成纤维细胞的药物 作为侵袭性成纤维细胞。我们在R35申请中提出的研究可能会为以下方面提供新的线索 我们还没有意识到治疗性干预，我们希望有自由追求这些干预。 此外，长期资助这一奖项的好处使我能够培训下一代 科学家们，就像我在杜克大学和目前在雪松这里所做的那样。

ABSTRACT Our laboratory has been focused on elucidating the molecular mechanisms that regulate progressive pulmonary fibrosis for over two decades. My contributions to the field of idiopathic pulmonary fibrosis research include using matrix hyaluronan as a model molecule to dissect the molecular mechanisms of progressive lung fibrosis. We have identified the role of hyaluronan fragments in regulating lung inflammation. We discovered that hyaluronan and hyaluronan receptors have roles in lung inflammation and in lung stem cell regeneration. We discovered an invasive fibroblast phenotype in mice as well as in idiopathic pulmonary fibrosis explants. We are generally credited with expanding the notion that matrix is more than just glue and has a dynamic role in regulating lung biology. One aspect of our work that I have been proud of is that we have published much of our science in non-subspecialty journals of reasonable impact. This suggests that although we study the lung, the concepts we have put forward have been deemed of interest to a broader audience. The goals of this R35 application are to identify the epithelial-mesenchymal interactions that lead to unremitting fibrosis. Specifically, we propose in this R35 to identify mechanisms for AEC2 failed regenerative capacity in mouse and man, to identify mechanisms for mesenchymal expansion in mice with impaired AEC2 renewal capacity, to identify the mechanisms by which beta-arrestin1 and CD44 regulate the invasive fibroblast phenotype, and to identify mechanisms by which the invasive fibroblast impairs AEC2 cell renewal. Augmenting scientific knowledge in understanding the underlying mechanisms and the mode of actions of these interactions in lung fibrosis could significantly aid therapeutic development for patients with progressive pulmonary fibrosis. My belief is that we need a drug that promotes alveolar progenitor cells renewal and a drug that targets pathogenic fibroblasts such as invasive fibroblasts. The studies that we propose in this R35 application may suggest new leads for therapeutic intervention we are not yet aware of and we want to have the freedom to pursue them. Furthermore, the benefit of longer-term funding of this award allows me to train the next generation of scientists as I have done during my time at Duke University as well as currently here at Cedars.