Molecular Regulation of Progressive Pulmonary Fibrosis

进行性肺纤维化的分子调控

• 批准号: 10579263
• 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/10579263
• 关键词: Alveolar; Award; Awareness; Belief; Biology; CD44 Antigens; CD44 gene; Cells; Drug Targeting; Epithelium; Fibroblasts; Fibrosis; Freedom; Funding; Glues; Goals; Hyaluronan; Impairment; Journals; Knowledge; Laboratories; 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; beta-arrestin; 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.

抽象的 我们的实验室集中于阐明调节进行性的分子机制 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的分子机制 纤维化。我们已经确定了透明质酸碎片在调节肺部炎症中的作用。我们发现了 透明质酸和透明质酸受体在肺部炎症和肺部干细胞再生中起作用。 我们在小鼠以及特发性肺纤维化外植体中发现了一种侵入性的成纤维细胞表型。 我们通常认为扩大矩阵不仅仅是胶水，并且具有动态角色的观念。 在调节肺生物学方面。我为自己感到骄傲的工作的一个方面是，我们已经发表了很多 我们在合理影响的非掩饰期刊上的科学。这表明，尽管我们研究肺，但 我们提出的概念被认为是更广泛的受众兴趣。 R35的目标 应用是确定导致纤维化无关的上皮 - 间质相互作用。具体来说， 我们建议在此R35中确定小鼠和人的AEC2再生能力失败的机制， 确定AEC2更新能力受损的小鼠中间充质扩张的机制，以识别 Beta-arrestin1和CD44调节侵入性成纤维细胞表型的机制，并识别 侵入性成纤维细胞会损害AEC2细胞更新的机制。增强科学知识 了解肺纤维化中这些相互作用的基本机制和作用方式 为进行性肺纤维化的患者提供了明显的治疗性发育。我的信念是我们 需要一种促进肺泡祖细胞更新的药物，并针对致病性成纤维细胞的药物 作为侵入性成纤维细胞。我们在此R35应用中提出的研究可能建议 我们尚未意识到的治疗干预措施，我们希望自由地追求它们。 此外，该奖项的长期资助的好处使我能够培训下一代 就像我在杜克大学（Duke University）以及目前在雪松（Cedars）的时候所做的那样。