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Sox9 Regulation of Fibroblast Activation and Pulmonary Fibrosis

Sox9 对成纤维细胞活化和肺纤维化的调节

基本信息

批准号：
10461725
负责人：
Satish K Madala
金额：
$ 3.7万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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：
2021-08-15 至 2022-07-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10461725
关键词：
Adult American Apoptosis Apoptotic Area Attenuated BCL1 Oncogene BCL2L1 gene Biochemical Biological Assay Bleomycin Cartilage Cell Survival Cells Cicatrix Cirrhosis Co-Immunoprecipitations Collagen Complex Coupled Data Deposition Development Diagnosis Disease Distal Extracellular Matrix Family Fibroblasts Fibrosis Future Gene Expression Gene Expression Profiling Generations Genes Genetic Transcription Goals Growth Factor HMG-Box Domains In Vitro Knowledge LOXL2 gene Laboratories Lead Lesion Luciferases Lung Lung diseases Maintenance Medical Mesenchymal Methods Modeling Molecular Morphogenesis Mus Myofibroblast Organ Pathogenesis Pathologic Pathologic Processes Pathway interactions Patients Peripheral Prevention Process Production Publishing Pulmonary Fibrosis Pulmonary Pathology Regulation Regulator Genes Research Resolution Respiratory Failure Role Severities Testing Time Tissues Transcriptional Regulation Transforming Growth Factor alpha Transforming Growth Factor beta Transgenic Mice Up-Regulation base chronic liver disease crosslink effective therapy epithelial stem cell experimental study fibrotic lung fibrotic lung disease gene network idiopathic pulmonary fibrosis improved in vivo in vivo Model innovation insight lung development lung lesion member migration mouse model multidisciplinary novel overexpression programs promoter pulmonary function selective expression transcription factor transcriptome translational study treatment strategy

项目摘要

PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease that is incurable and progressive due to fibroblast activation, and the formation of scar tissue. Approximately 130,000 Americans suffer from IPF, with an estimated 50,000 new cases diagnosed each year. Although it is well accepted that myofibroblast accumulation is a central component of pathogenesis in IPF, the transcriptional program(s) that orchestrate fibroblast activation including fibroblast-to-myofibroblast transformation (FMT), survival, migration and ECM organization are poorly defined and represent a significant knowledge gap in the field. Sox9 is a member of the HMG-box family of transcription factors that are selectively expressed by epithelial progenitor cells to modulate branching morphogenesis in the lung and the organized deposition of collagen as part of cartilage formation in multiple organs. However, the role of Sox9 in fibroblast activation has been poorly studied in adult fibrotic lung diseases. Our new findings have determined that Sox9 is upregulated in lung mesenchymal cells of IPF and functions as a positive regulator of FMT, myofibroblast survival, migration and ECM production. The loss of Sox9 expression has attenuated αSMA expression and myofibroblast transformation in mesenchymal cells isolated from IPF lungs and TGFα model. In support, a recent published study suggest Sox9 upregulation in patients with chronic liver disease that correlated with fibrosis severity and progression towards cirrhosis. Taken together, these findings lead us to postulate that Sox9 functions as a positive regulator of FMT, myofibroblast survival, migration, and ECM in the pathogenesis of pulmonary fibrosis. For this study, we propose three specific aims: 1) determine mechanisms by which Sox9 induces fibroblast activation; 2) establish in vivo the role of Sox9-expressing mesenchymal cells in the pathogenesis of pulmonary fibrosis; and 3) identify mechanisms by which Sox9 augments myofibroblast survival and the progression of established and ongoing pulmonary fibrosis. We will use advanced molecular methods and mouse transgenic approaches, coupled with detailed biochemical analysis of these Sox9-driven processes in vivo and in vitro. Completion of the proposed experiments is likely to impart a significant understanding of Sox9-driven fibroblast activation. The multidisciplinary team will facilitate a timely approach with expertise in all aspects of lung pathology and support future translational studies in IPF. Our approach is innovative due to the generation of novel transgenic mice to test mesenchymal cell-specific functions of Sox9 in pulmonary fibrosis. The proposed research is significant in that completion of this study will increase an understanding of the mechanisms causing fibroblast activation in IPF, which in turn will lead to advanced medical therapies for the treatment and possible cure or prevention of this debilitating lung disease.

项目总结