Environmental effects on lupus T cell DNA methylation and gene expression

环境对狼疮 T 细胞 DNA 甲基化和基因表达的影响

• 批准号: 7645044
• 负责人: BRUCE C. RICHARDSON
• 金额: $ 35.67万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645044
• 关键词: Affect; Age; Aging; Autoimmunity; DNA; DNA Methylation; DNA Modification Methylases; Defect; Development; Diet; Diet Modification; Dietary Supplementation; Disease; Endothelial Cells; Folate; Gene Expression; Genes; Human; Hydralazine; Immune system; In Vitro; Individual; Interferon Type II; Lead; Lupus; Methionine; Methylation; Modeling; Monozygotic twins; Mus; Myocardial Infarction; Nutrient; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pisum sativum; Play; Prevention; Principal Investigator; Procainamide; Reporting; Role; Severities; Severity of illness; Signal Pathway; Signal Transduction; Subarachnoid Hemorrhage; Supplementation; Systemic Lupus Erythematosus; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transferase; Ultraviolet Rays; Unstable angina; Xenobiotics; acute coronary syndrome; autoreactive T cell; autoreactivity; base; cytotoxic; cytotoxicity; drug induced lupus; environmental agent; enzyme activity; genetic element; inhibitor/antagonist; insight; lupus-like; macrophage; meetings; overexpression; perforin; prevent; programs

DESCRIPTION (provided by applicant): Hypomethylated T cells aberrantly overexpressing the methylation sensitive genes CD11a, IFN-gamma, perform and CD70 have been implicated in the pathogenesis of human lupus. Recent studies from this group demonstrate that KIR genes, implicated in acute coronary syndromes (unstable angina and myocardial infarctions), are also methylation sensitive and overexpressed on lupus T cells. Preliminary studies suggest that methylation sensitive T cell gene expression can be increased by restricting either folate or Met, or by decreasing DNA methyl transferase (DNMT) enzyme activity with direct/specific inhibitors, signaling inhibitors, or SAH, and that these effects are additive. Further, supplementation with either Met or folate decreases or prevents overexpression of the methylation sensitive genes by these inhibitors. These results suggest that decreases in DNMT expression due to environmental xenobiotics affecting transferase levels or function, together with dietary influences, are additive in affecting methylation sensitive gene expression, and ultimately causal in the development of lupus and its complications. These results also suggest that dietary supplementation of one or more nutrients involved in DNA methylation may be protective. These hypotheses will be tested by comparing the effects of: 1) nutrient restriction/supplementation and DNA methylation inhibitors alone and in combination on the expression and methylation of T cell CD11a, CD70, IFN-gamma, perforin and KIR and determining the consequences on cytotoxicity for macrophages and endothelial cells, 2) nutrient restriction and supplementation in vitro on the expression and methylation of methylation sensitive genes in T cells from subjects with lupus and normal controls, and 3) control, methyl-donor deficient, and methyl-rich diet on the expression of methylation sensitive T cell genes and lupus severity in mice with autoimmunity caused by an inducible ERK pathway signaling defect. Evidence that dietary modification can ameliorate aberrant gene expression in vitro and disease severity in the murine model will lead to studies extending these results to lupus patients.

描述（由申请人提供）： 异常过表达甲基化敏感基因CD11a，IFN-GAMMA，Perform和CD70的T甲基化T细胞与人类狼疮的发病机理有关。该组的最新研究表明，涉及急性冠状动脉综合征（不稳定的心绞痛和心肌梗死）的KIR基因也对狼疮T细胞敏感且过表达。初步研究表明，可以通过限制叶酸或MET或通过直接/特定抑制剂，信号抑制剂或SAH降低DNA甲基转移酶（DNMT）酶活性来增加甲基化敏感的T细胞基因表达，或者通过降低DNA甲基转移酶（DNMT）酶活性，并且这些作用是添加的。此外，补充MET或叶酸可减少或防止这些抑制剂对甲基化敏感基因的过表达。这些结果表明，由于影响转移酶水平或功能以及饮食影响的环境异种生物引起的DNMT表达降低，在影响甲基化敏感基因表达以及最终导致狼疮及其并发症的发展中是累加的。这些结果还表明，对DNA甲基化涉及的一种或多种营养素的饮食补充可能具有保护作用。这些假设将通过比较：1）单独的养分限制/补充和DNA甲基化抑制剂，以及对T细胞CD11A，CD70，IFN-Gamma，Perforin和Kir和Kir和Kir的表达和甲基化的结合，并确定对巨噬细胞的抑制作用，2）的影响，并确定对巨噬细胞的影响，2）来自患有狼疮和正常对照的受试者的T细胞中的甲基化敏感基因的甲基化敏感基因，以及3）对照，甲基抑制缺乏和富含甲基化的饮食对甲基化敏感T细胞基因的表达和狼疮的表达，而狼疮在自身免疫性中由诱导的ERK途径途径缺陷引起的自身免疫性。在鼠模型中，饮食改性可以改善体外和疾病严重程度的异常基因表达的证据将导致研究将这些结果扩展到狼疮患者。