Molecular Regulation of Progressive Pulmonary Fibrosis

进行性肺纤维化的分子调控

• 批准号: 10352422
• 负责人: Paul Wesley Noble
• 金额: $ 84.75万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352422
• 关键词: Alveolar; Award; Awareness; Belief; Biology; CD44 Antigens; CD44 gene; Cells; Drug Targeting; Epithelial; Fibroblasts; Fibrosis; Freedom; Funding; Glues; Goals; Hyaluronan; Impairment; Journals; Knowledge; Laboratories; Lead; Lung; Mesenchymal; Modeling; Molecular; Mus; Pathogenicity; Patients; Pharmaceutical Preparations; Phenotype; Publishing; Pulmonary Fibrosis; Pulmonary Inflammation; Regenerative capacity; Regulation; Research; Role; Science; Scientist; Therapeutic Intervention; Time; Training; Universities; Work; idiopathic pulmonary fibrosis; interest; man; next generation; stem cell self renewal; stem cells; therapeutic development

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.

摘要 我们的实验室一直致力于阐明调节进行性 肺纤维化超过二十年。我对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行性肺损伤的分子机制， 纤维化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。 我们通常被认为扩展了矩阵不仅仅是胶水的概念，并且具有动态作用 在调节肺部生物学方面。我们工作的一个方面，我一直感到自豪的是，我们已经发表了许多 我们的科学在非子专业期刊的合理影响。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。R35的目标 应用是鉴定导致持续纤维化的上皮-间充质相互作用。具体地说， 我们在这篇R35中提出，要确定小鼠和人类中AEC 2再生能力失败的机制， 确定AEC 2更新能力受损的小鼠中间充质扩增的机制， β-arrestin 1和CD 44调节侵袭性成纤维细胞表型的机制，并鉴定 侵袭性成纤维细胞损害AEC 2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， 显著地有助于进行性肺纤维化患者治疗发展。我相信我们 我需要一种促进肺泡祖细胞更新的药物和一种靶向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： 我们还没有意识到的治疗干预，我们希望有追求它们的自由。 此外，这个奖项的长期资助的好处使我能够培养下一代的 我在杜克大学和目前在雪松大学所做的一切。