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

项目摘要 特发性肺纤维化(IPF)是一种进行性间质性肺疾病，中位生存期为2-5年。 IPF的发病率随着年龄的增长而增加，因此随着人口的不断增长，IPF将影响更多的人 年纪更大了。除肺移植外，目前尚无有效治疗IPF的方法。我们目前对IPF的理解 提示当环境因素改变正常的肺内环境平衡时，发病机制就开始了 或表观遗传易感个体。这种状态的改变扰乱了正常的细胞通讯，并诱导了 伤口愈合反应，最终导致肺实质不可逆转的纤维化。尽管完全相同的 IPF的病因尚不清楚，促纤维化的巨噬细胞参与了疾病的发病机制。初步 数据表明，IPF患者有一群疾病特异性巨噬细胞。这项建议旨在 阐明特异组蛋白修饰在IPF中疾病特异性巨噬细胞转录组中的作用。目标1 结合生化和遗传工具来确定IPF中组蛋白修饰的靶点和调节因子- 特定的巨噬细胞。目标2将评估存在或不存在直接引起的转录变化 巨噬细胞中的组蛋白修饰。这些实验将阐明巨噬细胞的一种机制 对IPF患者有直接翻译影响的功能障碍。

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.