Elucidating the epigenetic regulation of extracellular matrix and virus-induced fibroblast activation

阐明细胞外基质和病毒诱导的成纤维细胞活化的表观遗传调控

• 批准号: 10572863
• 负责人: Jaye C Gardiner
• 金额: $ 12.5万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572863
• 关键词: 2019-nCoV; ATAC-seq; Affect; Applied Skills; Bacterial Infections; Binding; Binding Proteins; Biological Markers; Categories; Cells; Cellular biology; ChIP-seq; Chemicals; Chromatin; Chronic Obstructive Pulmonary Disease; Communication; Complex; Connective Tissue; Coxsackie B Viruses; Cues; DNA-Directed RNA Polymerase; Data; Deposition; Development; Disease; Environment; Epigenetic Process; Excision; Extracellular Matrix; Failure; Fibroblasts; Fibrosis; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Grant; Growth Factor; Hepatitis B Virus; Histone Acetylation; Human; In Vitro; Infection; Inflammatory Response; Influenza A virus; Knockout Mice; Lead; Link; Liver Fibrosis; Malignant Neoplasms; Mediating; Mesenchymal; Molecular; Myofibroblast; Nucleosomes; Organ; Organ failure; Pancreas; Pancreatitis; Pathologic; Patient Isolation; Phenotype; Play; Predisposition; Process; Pulmonary Fibrosis; Regulation; Reporting; Research; Resolution; Respiratory Tract Infections; Respiratory syncytial virus; Role; Signal Transduction; Simplexvirus; Specificity; Stimulus; Testing; Time; Tissue Sample; Tissues; Transcription Coactivator; Transcription Initiation; Transforming Growth Factor beta; Tropism; Viral; Virus; Virus Diseases; Work; brahma; chromatin remodeling; clinically relevant; cytokine; epigenetic memory; epigenetic regulation; experimental study; extracellular; falls; human pathogen; idiopathic pulmonary fibrosis; in vivo; innovation; insight; interstitial; memory acquisition; mouse model; netrin-G1; novel; pancreatic cancer patients; programs; recruit; repaired; response; skill acquisition; small molecule inhibitor; therapeutic target; tissue repair; transcriptome sequencing; virology; wound healing

PROJECT SUMMARY While wound healing processes are vital for successful organismal tissue repair, failure to turn off these mechanisms lead to the excessive accumulation of the extracellular matrix (ECM) and the development of fibrosis. Although recent research is beginning to illuminate the circumstances that allow for fibrosis resolution, most fibrotic conditions remain unresolved; resulting in organ failure or a predisposition to cancer. While the triggers for fibrotic diseases fall within a handful of categories, including viral/bacterial infection, tissue damage, and chemical insults, all induce the sustained activation of mesenchymal cells into myofibroblasts. Besides transforming growth factor β (TGF-β), which is a major activator of fibroblasts, the ECM also has the ability to alter a fibroblast’s activation state. We and others have demonstrated that this activated phenotype can persist despite the cell’s removal from fibrotic tissues, suggesting that fibroblasts have an “epigenetic memory” acquired during activation and retained thereafter. However, the molecular details underlying epigenetic regulation during myofibroblastic activation and whether these details are universal despite the activation trigger is unknown. One potential mechanism of myofibroblast regulation is through the ECM-dependent expression of pro- fibrotic genes. Gene expression is a tightly regulated process that requires chromatin remodeling, binding of transcriptional activators, and recruitment of RNA polymerase to initiate transcription. As such, the structural reorganization of the chromatin plays a large role in the temporal regulation and tissue specificity of gene expression. Brahma-related gene 1 (BRG1) is a central catalytic ATP-subunit of the BAF (BRG1/BRM1- associated factor) complex which works to drive chromatin accessibility via nucleosome eviction. BRG1 has also been shown to regulate ECM gene expression in both healthy and virally-induced fibrotic contexts. Moreover, preliminary data found that BRG1-deficient pancreatic fibroblasts lost the expression of a key functional regulator, Netrin G1. Taken together, this suggests a role of BRG1 in regulating myofibroblast pro-fibrotic genes. The overarching goal of this proposal is to test the hypothesis that the ECM and fibrosis-inducing viruses alter fibroblasts’ chromatin landscape in a BRG1-dependent manner and contribute to the epigenetic memory that underlies myofibroblastic function. To test this hypothesis, Aim 1 will first investigate BRG1’s involvement in pancreatic fibroblast activation in vitro and whether this is regulated by ECM-mediated signaling. In Aim 2, experiments will focus on the role of BRG1 in regulating disease formation by using an in vivo pancreatitis mouse model. Finally, Aim 3 will build on these lessons and investigate the mechanisms by which fibrosis-inducing viruses cause myofibroblast activation, beginning with the frequent human pathogen, Influenza A virus. By using a novel perspective to understanding fibrosis, this research provides insights that will advance cell biology, epigenetics, and virology, as well as reveal how the ECM/viruses create a pro-fibrotic state.

项目总结