Role of cleaved H3 as a key epigenetic regulator of macrophages in idiopathic pulmonary fibrosis

裂解 H3 作为巨噬细胞关键表观遗传调节剂在特发性肺纤维化中的作用

• 批准号: 10410347
• 负责人: Madeleine Scott
• 金额: $ 3.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-14 至 2022-06-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410347
• 关键词: Address; Affect; Age; Biochemical Genetics; CRISPR screen; CRISPR/Cas technology; Cell Communication; Cell Differentiation process; Cell Line; Cells; ChIP-seq; Chromatin; Cicatrix; Cleaved cell; Collagen; Cytometry; DNA Sequence; Data; Deposition; Diagnosis; Disease; Disease Progression; Environmental Risk Factor; Epigenetic Process; Etiology; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Histone H3; Histones; Homeostasis; Incidence; Individual; Interstitial Lung Diseases; Knock-out; Knowledge; Length; Libraries; Lung; Lung Transplantation; Lung diseases; Measures; Mediating; Metals; Myelogenous; Normal Cell; Pathogenesis; Patients; Peptide Hydrolases; Persons; Population; Prevalence; Proteins; Pulmonary Fibrosis; Role; Structure of parenchyma of lung; Techniques; Technology; Threonine; Time; Tissues; United States; Work; antibody conjugate; base; cell type; curative treatments; differential expression; effective therapy; experimental study; genetic signature; histone modification; idiopathic pulmonary fibrosis; macrophage; overexpression; response; single-cell RNA sequencing; tobacco control; tobacco etch virus; tool; transcriptome; transcriptome sequencing; transcriptomics; wound healing

Project Summary Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a median survival of 2-5 years. The incidence of IPF increases with age, thus IPF will affect more individuals as the population continues to grow older. There is no effective treatment for IPF except lung transplantation. Our current understanding of IPF suggests that pathogenesis begins when environmental factors alter normal lung homeostasis in a genetically or epigenetically susceptible individual. This altered state disrupts normal cell communication and induces a wound healing response, ultimately leading to irreversible fibrosis of the lung parenchyma. Although the exact etiology of IPF is unknown, pro-fibrotic macrophages have been implicated in disease pathogenesis. Preliminary data suggests that patients with IPF have a population of disease-specific macrophages. This proposal aims to elucidate the role of specific histone modifications on disease-specific macrophage transcriptome in IPF. Aim 1 combines biochemical and genetic tools to identify the targets and regulators of histone modifications in IPF- specific macrophages. Aim 2 will evaluate the transcriptional changes directly caused by presence or absence of a histone modification in macrophages. These experiments will elucidate a mechanism of macrophage dysfunction with direct translational implications for patients with IPF.

项目摘要 特发性肺纤维化（IPF）是一种进行性间质性肺病，中位生存期为2-5年。 IPF的发病率随着年龄的增长而增加，因此随着人口的持续增长，IPF将影响更多的个体 老了除肺移植外，IPF尚无有效治疗方法。我们目前对IPF的理解 提示发病机制始于环境因素改变正常的肺内稳态， 或表观遗传易感个体。这种改变的状态破坏了正常的细胞通讯， 创伤愈合反应，最终导致肺实质的不可逆纤维化。虽然确切的 IPF的病因尚不清楚，促纤维化巨噬细胞与疾病发病机制有关。初步 数据提示IPF患者具有疾病特异性巨噬细胞群。这项建议旨在 阐明特异性组蛋白修饰对IPF中疾病特异性巨噬细胞转录组的作用。要求1 结合生物化学和遗传学工具，以确定IPF中组蛋白修饰的靶点和调节剂， 特异性巨噬细胞目的2将评估直接由存在或不存在引起的转录变化 巨噬细胞中的组蛋白修饰。这些实验将阐明巨噬细胞 对IPF患者有直接翻译影响的功能障碍。