Mesenchymal modulation of epithelial metaplasia in lung fibrosis

肺纤维化中上皮化生的间充质调节

基本信息

批准号：
10095587
负责人：
Tien Peng
金额：
$ 58.65万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10095587
关键词：
Address Alveolar Antigens Appearance Area BMP4 BMPR1A gene Basal Cell Bioinformatics Biological Assay Cells Cicatrix Clinical Data Deposition Disease Epithelial Erinaceidae Feedback Fibrosis Genetic Human Immune In Vitro Injury Ligands Lung Mesenchymal Mesenchyme Metaplasia Modeling Mus Organ Organoids Outcome Pathologic Patients Pharmacology Physiology Process Protein Engineering Proteins Pulmonary Fibrosis Recombinants Role Sampling Severity of illness Signal Transduction Site Testing Up-Regulation analysis pipeline cell type clinically relevant extracellular genetic approach idiopathic pulmonary fibrosis in vivo in vivo evaluation inhibitor/antagonist insight loss of function lung injury mortality mouse model novel pre-clinical progenitor pulmonary function repaired reverse genetics screening stem cell population targeted treatment therapeutic target tool transcriptome sequencing

项目摘要

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.

项目概要/摘要异常的上皮重编程可以采取化生的形式，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，这通常达到顶峰在由充满基质的疤痕和化生上皮组成的转化屏障中。一个特征性的特发性肺纤维化 (IPF) 的特征是 KRT5+ 基底细胞异位出现受损的肺泡室，其存在与疾病的严重程度和生存率相关。这表明化生是肺纤维化的临床相关特征，并了解这种病理学上皮可塑性的形式可能提供潜在的治疗靶点。我们之前已经证明了刺猬 (Hh) 激活的间充质有助于纤维化修复中的疤痕成分。我们现在证明 Hh 激活的间充质与气道祖细胞功能性相互作用，以促进纤维化肺中的化生 KRT5 分化。此外，我们还发现 Hh-BMP 信号传导气道祖细胞生态位中的回路调节纤维化修复过程中的化生结果。我们的中央假设间充质 Hh 激活上调祖细胞生态位中的 BMP 拮抗剂，它驱动人类和小鼠肺部的上皮化生，并且该 Hh-BMP 电路可以旨在减轻和逆转肺纤维化的化生。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，以及我们对人类的访问样本，该提案旨在解决祖细胞生态位的间充质区室如何改变纤维化修复中的上皮可塑性，并概述了潜在的临床前管道来识别可以靶向肺纤维化中的上皮化生的化合物。