Histone H4 Lysine16 Acetylation in Aging and Lung Fibrosis

衰老和肺纤维化中的组蛋白 H4 赖氨酸 16 乙酰化

基本信息

批准号：
9275907
负责人：
Yan Sanders
金额：
$ 30.14万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275907
关键词：
Acetylation Affect Age Age of Onset Aging Animals Apoptosis Bleomycin Cell physiology Cells Chromatin Structure Collagen DNA Methylation Data Deacetylase Disease Epigenetic Process Equilibrium Etiology Fibroblasts Fibrosis Gene Expression Genes Genetic Transcription HDAC1 gene HDAC2 gene Hamman-Rich syndrome Histone Deacetylase Histone H4 Histones Incidence Injury Knock-out Knowledge Lead Lung Mammals Mediating Methods Modeling Modification Mus Pathogenesis Phenotype Predisposition Prevalence Process Pulmonary Fibrosis Resistance Resolution Role Sampling Stress Testing Therapeutic Time Translating Up-Regulation age related aged environmental stressor epigenetic regulation histone acetyltransferase histone modification insight juvenile animal lung injury male molecular targeted therapies mortality mouse model normal aging novel therapeutic intervention novel therapeutics public health relevance response senescence therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is an age related fatal disease with unknown etiology. Its incidence increases with age, environmental effects is important. Epigenetic changes, including DNA methylation and histone modifications, are major causes of age-related diseases. Environmental stressors and aging contribute to histone modifications. Epigenetic modifications are potentially reversible. We and others have established that epigenetic mechanisms participate in the pathogenesis of IPF. Aging may potentiate the susceptibility to environmental stress by modulating pro-fibrotic cellular phenotypes in IPF. However, studies of epigenetic regulation, in particular histone modifications and their related cellular phenotypes in the aging lung and in IPF are lacking. Chromatin structure, which is affected by histone modifications, is an important determinant of the cell phenotype. The active histone mark H4K16Ac epigenetically regulates gene expression. Our preliminary data demonstrated the dysregulation of this histone modification in IPF fibroblasts. We hypothesize that age-related histone modifications, in particular H4K16Ac, mediates fibrotic cell phenotype, promotes senescence and induced apoptosis resistant lung fibroblasts that leads to persistent fibrosis in aging. Targeting this histone modification will alter pro-fibrotic ell phenotypes and promote resolution of fibrosis. Our specific aims are: (1) Determine mechanisms that regulate H4K16Ac in persistent lung fibrosis associated with aging. (2) Determine the role of H4K16Ac in regulating pro-fibrotic phenotypes in fibrotic lung fibroblasts. (3) Determine the efficacy of targeting H416Ac in an aging mouse model of persistent lung fibrosis. The proposed studies will define the role of age-related histone modification H4K16Ac in the pathogenesis of IPF, and translate that knowledge to novel therapeutic interventions for pulmonary fibrosis.

描述（由申请人提供）：特发性肺纤维化（IPF）是一种与年龄相关的致命疾病，其发病率随着年龄的增长而增加，包括DNA甲基化和组蛋白修饰在内的表观遗传变化是导致年龄增长的主要原因。我们和其他人已经确定表观遗传机制参与了 IPF 的发病机制。然而，对表观遗传调控的研究，特别是衰老肺和 IPF 中的组蛋白修饰及其相关细胞表型，受组蛋白修饰影响。活性组蛋白标记 H4K16Ac 是细胞表型的重要决定因素。我们的初步数据表明，IPF 成纤维细胞中的这种组蛋白修饰失调。与年龄相关的组蛋白修饰，特别是 H4K16Ac，介导纤维化细胞表型，促进衰老并诱导抗凋亡肺成纤维细胞，从而导致衰老过程中的持续纤维化。针对这种组蛋白修饰将改变促纤维化细胞表型并促进纤维化的消退。目标是：(1) 确定调节 H4K16Ac 在与衰老相关的持续性肺纤维化中的作用。 H4K16Ac 调节纤维化肺成纤维细胞中的促纤维化表型 (3) 确定在持续性肺纤维化的衰老小鼠模型中靶向 H416Ac 的功效拟议的研究将确定年龄相关的组蛋白修饰 H4K16Ac 在 IPF 发病机制中的作用。，并将这些知识转化为肺纤维化的新型治疗干预措施。