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Deciphering the role of p16INK4A+ fibroblasts in lung fibrosis

解读 p16INK4A 成纤维细胞在肺纤维化中的作用

基本信息

批准号：
10559515
负责人：
Tien Peng
金额：
$ 55.69万
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：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10559515
关键词：
3-Dimensional Acceleration Address Adoptive Cell Transfers Adoptive Transfer Aging Alveolus Area Biological Assay Biological Markers Biology CDKN2A gene Cell Cycle Arrest Cell Line Cell Separation Cells Characteristics Chemicals Chronic lung disease Cicatrix Collagen Cues Data Disease Disease model Drug Screening Elderly Engineering Epithelium Exhibits Fibroblasts Fibrosis Genetic Genetic Models Human Image In Vitro Induction of Apoptosis Inflammatory Injury Knowledge Ligands Lung Maintenance Metaplasia Methodology Modeling Morphology Mus Organ Organoids Outcome Pathogenesis Pathologic Pathology Phenotype Physiological Process Pulmonary Fibrosis Regenerative response Reporter Reporting Risk Factors Role Testing Therapeutic Time Tissues Traction Transplantation Tumor Suppressor Proteins Uncertainty Validation age related aged cell behavior cell type combinatorial defined contribution epithelial stem cell fibrotic lung fibrotic lung disease functional decline genetic approach high throughput screening idiopathic pulmonary fibrosis in vivo lung injury migration novel progenitor programs prospective rational design regenerative cell response screening senescence single cell analysis single-cell RNA sequencing stem cells therapeutic target tool tumorigenesis wound healing

项目摘要

Project Summary/Abstract Aging is one of the biggest risk factors for many chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). However, uncertainties remain as to how age-related processes contribute to the pathogenesis of IPF, particularly in deciphering the cell types that might play a role in both aging and fibrotic transformation. Senescence, a cellular state characterized by an irreversible cell cycle arrest and other morphologic transformations, is thought to be a cellular phenotype that becomes increasingly prevalent in aged organs, contributing to the decline in function over time. p16INK4A, a tumor suppressor, is one of the best-studied biomarkers of senescent cells in vitro and in vivo. Numerous genetic models have been built to remove p16INK4A+ cells from tissues, demonstrating a functional role for these cells in promoting age-related pathologies such as lung fibrosis. Despite the knowledge gained from strategies that remove p16INK4A+ cells, deletion of these cells precludes the identification and functional characterization of p16INK4A+ cells in vivo, leaving a large gap in our understanding of how senescent cells might behave in tissues rather than in a culture dish. To address this, we constructed a novel genetic reporter of senescence by engineering an amplified fluorescent tag driven by expression of p16INK4A (mouse referred to as INK4A H2B-GFP Reporter-In-Tandem, or INKBRITE) to isolate and characterize p16INK4A+ cells in vivo and ex vivo. To our surprise, we were able to identify p16INK4A+ fibroblasts in young and healthy lungs that contribute to scar-forming cells in areas of fibrotic remodeling. Furthermore, p16INK4A+ cells are able to alter the epithelial progenitor microenvironment and alter stem cell regenerative outcomes. This led us to the hypothesis that p16INK4A+ fibroblasts are capable of contributing to fibrosis by forming scars and inducing an pathologic epithelial response, and the INKBRITE reporter could be leveraged as a screening platform to identify compounds that more precisely target p16INK4A+ fibroblasts in vivo. Through the use of single cell RNA sequencing, adoptive cell transfers, lineage tracing, high-content imaging, and various methodologies outlined in this proposal, we aim to better define the cellular contribution of p16INK4A+ fibroblasts to fibrotic transformation, and define agents that might better remove it from tissues.

项目总结/文摘