Mesenchymal modulation of epithelial metaplasia in lung fibrosis

项目概要/摘要 异常的上皮细胞重编程可以以化生的形式出现，其特征是 通常不存在于损伤部位的成熟细胞类型。在器官纤维化中， 在一个由充满基质的疤痕和化生上皮组成的转化屏障中。一种特异症 特发性肺纤维化（IPF）的特征是KRT 5+基底细胞在肺组织中的异位出现。 肺泡隔室受损，其存在与疾病严重程度和存活率相关。这 表明化生是肺纤维化的临床相关特征， 上皮可塑性的形式可能是潜在的治疗靶点。我们之前已经证明， 刺猬（Hh）激活的间充质有助于纤维化修复中的瘢痕成分。我们现在 证明Hh激活的间充质在功能上与气道祖细胞相互作用， 在纤维化肺中的化生KRT 5分化。此外，我们还发现，Hh-BMP信号 气道祖细胞龛中的回路调节纤维化修复过程中的化生结果。我们的中央 假设是间充质Hh活化上调了祖细胞龛中的BMP拮抗剂， 在人类和小鼠的肺部都能驱动上皮化生，这种Hh-BMP回路可以 靶向减轻和逆转肺纤维化中的化生。利用新的遗传学/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，以及我们对人类的访问， 样本，这项建议的目的是解决如何间充质隔室的祖生态位 改变纤维化修复中的上皮可塑性，并概述了一个潜在的临床前管道，以确定 可以靶向肺纤维化中的上皮化生的化合物。

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.