Epigenetic regulation of cyclooxygenase-2 expression in systemic sclerosis lung fibroblasts

系统性硬化症肺成纤维细胞环氧合酶2表达的表观遗传调控

• 批准号: G1000440/1
• 负责人: Robin McAnulty
• 金额: $ 36.14万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1000440%2F1
• 关键词: Epigenetic; regulation; cyclooxygenase; expression; systemic

Systemic sclerosis (SSc) is a chronic multi-system disease that has a significant effect on quality of life and leads to premature death. Uncontrolled scarring, termed fibrosis, is one of the major characteristic features of this disease and occurs in the lungs in up to 80% of individuals with SSc. Although treatment for some manifestations of SSc has improved, there is no effective therapy for lung fibrosis, other than transplantation, and lung disease is the major cause of death in SSc. Further studies are therefore needed to understand the mechanisms involved in the development and progression of lung fibrosis in SSc in order to identify and develop new effective therapies.We have previously shown that lack of an enzyme called cyclooxygenase-2 (COX-2), plays important roles in the development of lung fibrosis associated with SSc. Recently we have found that this deficiency in COX-2 can be overcome by treating cells with drugs, called methyltransferase inhibitors and that this restores normal functions to the cells. These drugs block the chemical modification (methylation) of portions of DNA (genes) and some proteins in the cell nucleus, called histones, that can prevent production of proteins and enzymes like COX-2. Using a unique resource of cells obtained from the lungs of individuals with SSc, we aim to identify the mechanisms by which these methyltransferase inhibitors restore COX-2 production and normal cell function. Specifically we will determine whether this occurs through methylation of DNA or proteins and which genes or proteins are involved.The discovery that COX-2 production and function in cells, obtained from the lungs of patients with SSc, can be restored by methyltransferase inhibitors is of particular importance since drugs of this type are currently in use for the treatment of some cancers. Therefore greater understanding of the mechanisms involved would provide a strong basis for the use of these drugs in clinical trials for the treatment of SSc.

全身性硬化症（SSC）是一种慢性多系统疾病，对生活质量产生重大影响并导致过早死亡。不受控制的疤痕，称为纤维化，是该疾病的主要特征之一，发生在多达80％的SSC患者中。尽管对SSC的某些表现的治疗有所改善，但除了移植以外，没有有效的肺纤维化治疗，而肺病是SSC中死亡的主要原因。因此，需要进一步的研究来了解SSC中肺纤维化发展和进展的机制，以识别和开发新的有效疗法。我们先前表明，缺乏称为环氧酶-2（COX-2）的酶，在与SSC相关的肺纤维化发展中起着重要作用。最近，我们发现COX-2中的这种缺乏可以通过用药物（称为甲基转移酶抑制剂）处理细胞来克服，并且可以恢复细胞的正常功能。这些药物阻止了DNA（基因）部分的化学修饰（甲基化）和称为组蛋白的某些蛋白质，可以防止蛋白质和酶（如COX-2）的产生。使用从具有SSC个体肺的肺部获得的独特资源，我们旨在确定这些甲基转移酶抑制剂恢复COX-2产生和正常细胞功能的机制。具体而言，我们将确定这是否是通过DNA或蛋白质的甲基化以及涉及哪些基因或蛋白质进行的。发现从SSC患者的肺肺中获得的COX-2产生和功能，可以通过甲基转移酶抑制剂来恢复，因为目前使用这种类型的药物来治疗某些Cancers的药物。因此，对所涉及机制的更多了解将为这些药物在临床试验中使用SSC提供强大的基础。