Histone H4 Lysine16 Acetylation in Aging and Lung Fibrosis

 描述（由申请方提供）：特发性肺纤维化（IPF）是一种病因不明的年龄相关致死性疾病。其发病率随年龄增长而增加，环境影响很重要。表观遗传变化，包括DNA甲基化和组蛋白修饰，是年龄相关疾病的主要原因。环境压力和老化有助于组蛋白修饰。表观遗传修饰可能是可逆的。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。衰老可能通过调节IPF中的促纤维化细胞表型而增强对环境应激的易感性。然而，缺乏对表观遗传调控的研究，特别是组蛋白修饰及其在衰老肺和IPF中的相关细胞表型。 受组蛋白修饰影响的染色质结构是细胞表型的重要决定因素。活性组蛋白标记H4K16Ac表观遗传地调节基因表达。我们的初步数据证明了IPF成纤维细胞中这种组蛋白修饰的失调。我们假设年龄相关的组蛋白修饰，特别是H4K16Ac，介导纤维化细胞表型，促进衰老和诱导抗凋亡肺成纤维细胞，导致老化中的持续纤维化。靶向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。我们的具体目标是：（1）确定H4K16Ac在与衰老相关的持续性肺纤维化中的调节机制。(2)确定H4 K16 Ac在调节纤维化肺成纤维细胞促纤维化表型中的作用。(3)确定靶向H416Ac在持续性肺纤维化的衰老小鼠模型中的功效。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。

 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.