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.

系统性硬化症（SSc）是一种慢性多系统疾病，对生活质量有显着影响并导致过早死亡。不受控制的疤痕形成（称为纤维化）是这种疾病的主要特征之一，高达 80% 的 SSc 患者会出现在肺部。尽管SSc的某些表现的治疗有所改善，但除了移植外，尚无有效的肺纤维化治疗方法，而肺部疾病是SSc死亡的主要原因。因此，需要进一步的研究来了解 SSc 肺纤维化发生和进展的机制，以便识别和开发新的有效疗法。我们之前已经表明，缺乏一种称为环加氧酶-2 (COX-2) 的酶，会影响 SSc 肺纤维化的发生和进展。在与 SSc 相关的肺纤维化的发展中发挥重要作用。最近我们发现，COX-2 的这种缺陷可以通过用甲基转移酶抑制剂药物治疗细胞来克服，从而恢复细胞的正常功能。这些药物可阻断部分 DNA（基因）和细胞核中某些蛋白质（称为组蛋白）的化学修饰（甲基化），从而阻止 COX-2 等蛋白质和酶的产生。我们利用从 SSc 患者肺部获得的独特细胞资源，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。具体来说，我们将确定这是否是通过 DNA 或蛋白质的甲基化发生的，以及涉及哪些基因或蛋白质。从 SSc 患者肺部获得的细胞中 COX-2 的产生和功能可以通过甲基转移酶抑制剂恢复，这一发现具有重要意义。由于此类药物目前用于治疗某些癌症，因此尤为重要。因此，更好地了解所涉及的机制将为在临床试验中使用这些药物治疗 SSc 奠定坚实的基础。