权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结/文摘