Mesenchymal modulation of epithelial metaplasia in lung fibrosis

项目摘要/摘要 异常的上皮重编程可采取化生的形式，其特征是出现 损伤部位通常不存在的成熟细胞类型。在器官纤维化中，这种情况通常达到顶峰。 在一个由基质疤痕和化生上皮组成的转化屏障中。病态的人 特发性肺纤维化(IPF)的特征是Krt5基底细胞在肺组织中的异位出现 肺泡间隔受损，其存在与疾病的严重程度和存活率相关。这 提示化生是肺纤维化的临床相关特征，并理解这一病理特征 上皮可塑性的形成可能成为潜在的治疗靶点。我们之前已经表明， Hedgehog(HH)激活的间充质有助于纤维化修复过程中瘢痕的成分。我们现在 证明HH激活的间充质与呼吸道祖细胞功能相互作用促进 纤维化肺中化生Krt5的分化。此外，我们还证明了HH-BMP信号 在纤维化修复过程中，气道祖细胞龛中的回路调节化生结果。我们的中央 假设是间充质HH激活上调了祖细胞利基中的BMP拮抗剂， 导致人类和小鼠肺上皮化生，这种HH-BMP循环可以 旨在减轻和逆转肺纤维化中的化生。利用新的遗传/药理学 我们开发的工具，我们的单一和批量RNAseq生物信息学能力，以及我们接触人类的途径 样本，这项建议旨在解决祖细胞生态位的间充质隔间 改变纤维化修复中的上皮可塑性，并勾勒出一条潜在的临床前管道以确定 可针对肺纤维化上皮化生的化合物。

Project Summary/Abstract Aberrant epithelial reprogramming can take the form of metaplasia, characterized by the appearance of mature cell types that are not normally present at the site of injury. In organ fibrosis, this often culminates in a transformed barrier composed of matrix-laden scars and metaplastic epithelium. A pathognomonic feature of idiopathic pulmonary fibrosis (IPF) is the ectopic appearance of KRT5+ basal cells in the damaged alveolar compartment, the presence of which correlates with disease severity and survival. This suggests that metaplasia is a clinically relevant feature of lung fibrosis, and understanding this pathologic form of epithelial plasticity could present potential therapeutic targets. We have previously shown that hedgehog (Hh)-activated mesenchyme contributes to components of the scar in fibrotic repair. We now demonstrate that Hh-activated mesenchyme functionally interacts with airway progenitors to promote metaplastic KRT5 differentiation in the fibrotic lung. Furthermore, we show that a Hh-BMP signaling circuit in the airway progenitor niche regulates the metaplastic outcome during fibrotic repair. Our central hypothesis is that mesenchymal Hh activation upregulates BMP antagonists in the progenitor niche, which drives epithelial metaplasia in both human and mouse lungs, and this Hh-BMP circuit can be targeted to mitigate and reverse metaplasia in lung fibrosis. Leveraging novel genetic/pharmacologic tools we have developed, our single and bulk RNAseq bioinformatics capacity, and our access to human samples, this proposal aims to address how the mesenchymal compartment of the progenitor niche modifies epithelial plasticity in fibrotic repair, and outlines a potential pre-clinical pipeline to identify compounds that can target epithelial metaplasia in lung fibrosis.