Exposure in Epigenetic Regulation of Immune Response in CBD

CBD 免疫反应的表观遗传调控暴露

• 批准号: 8816361
• 负责人: LISA A MAIER
• 金额: $ 42.57万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816361
• 关键词: Alleles; Amino Acids; Antigen Presentation; Antigen-Presenting Cells; Antigens; Azacitidine; Berylliosis; Beryllium; Biological Markers; Breathing; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Case-Control Studies; Cell Differentiation process; Cells; Chromatin; Chronic berylliosis; Cicatrix; DNA Methylation; Data; Decitabine; Development; Disease; Environment; Environmental Exposure; Epigenetic Process; Etiology; Evaluation; Exposure to; Folic Acid; Future; Gene Expression; Gene Expression Alteration; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Transcription; Genome; Genomic approach; Genomics; Glutamic Acid; Goals; Granuloma; Granulomatous; HLA-DPB1 gene; Health; Heritability; Immune; Immune Response Genes; Immune response; Immunophenotyping; Individual; Inherited; Life; Light; Lung; Lung diseases; Mediating; Methylation; Modification; Organ; Pathogenesis; Pathway interactions; Positioning Attribute; Predisposition; Prevalence; Proliferating; Qualifying; Recruitment Activity; Regulation; Risk; Risk Factors; Sampling; Site; T-Lymphocyte; Testing; base; chemokine; clinical care; cytokine; disorder risk; epigenetic regulation; epigenome; epigenomics; genome wide association study; genome wide methylation; genome-wide; histone methylation; histone modification; human subject; non-smoker; peripheral blood; public health relevance; pyrosequencing; targeted treatment; therapeutic target

DESCRIPTION (provided by applicant): The goal of this study is to define the environmentally induced epigenetic marks and their impact on gene expression that result in the granulomatous lung disease, chronic beryllium disease (CBD). The study relies on the expertise and strengths of our uniquely qualified investigative team. This study will define pathogenic pathways and risk factors for CBD, the precursor to this disease (beryllium sensitization; BeS) and similar environmentally induced diseases. Exposure to an inhaled Be antigen(s) in the setting of a genetically susceptible host, initiates a Th1 immune response, with antigen presentation occurring via HLA Class II on antigen presenting cell (APC) in the context of CD4+ T cells. Subsequently, CD4+ T cells and APCs are recruited to the lung, proliferate, produce cytokines and chemokine's, and eventually form granulomas. An increased prevalence of HLA-DPB1 alleles with a glutamic acid at amino acid position 69 (E69) is found in CBD and BeS This same polymorphism may be found in up to 40% of Be exposed workers without BeS or CBD, suggesting that other susceptibility factors or forms of genetic regulation must be important in disease pathogenesis, in addition to exposure. Growing data in other immune-mediated diseases suggests that epigenetic mechanisms in combination with genetic susceptibility and environment may help explain disease risk. Epigenetic modifications determine the Th1 versus Th2 immune response through DNA methylation and histone modifications of key genes such as FOXP3, and thus impact health and disease. To date epigenetic alterations have not been explored in environmentally induced granulomatous diseases. Our preliminary data demonstrate significant genome-wide DNA methylation differences in pivotal immune response genes and networks at the site of exposure and disease, the lung, in CBD compared to BeS. Based on this information, the overarching hypothesis for this proposal is that epigenetic mechanisms impact gene expression and immune cell differentiation, ultimately impacting the risk of granulomatous lung disease. Using an integrated genomic approach we will first define epigenetic alterations (genome wide methylation) in CD4+ lung cells, with and without beryllium exposure in a case control study of CBD, BeS and normal controls. Subsequently, we will determine functional methylation alterations that impact gene transcription, information which will expand our understanding of the pathogenesis of CBD. As demethylating agents, such as 5- azacytidine (AZA) and decitabine are currently being used to treat immune mediated diseases, we will evaluate changes in validated methylation and gene expression targets treating CBD, BeS and control CD4+ lung cells with demethylating (AZA) or methylating (folic acid) agents. This study will provide data relevant to this class of agents as targets for therapy. Furthermore, the information gained from this proposal will shed light on the pathogenesis of other exposure related non-infectious granulomatous diseases, and on genome-exposure relationships, as our understanding of the epigenome grows.

描述（由申请人提供）：本研究的目的是确定环境诱导的表观遗传标记及其对导致肉芽肿性肺病、慢性铍病（CBD）的基因表达的影响。这项研究依赖于我们独特的合格调查团队的专业知识和优势。这项研究将确定 CBD 的致病途径和危险因素，CBD 是这种疾病的前兆（铍致敏；BeS）和类似的环境诱发疾病。在遗传易感宿主的环境中暴露于吸入的 Be 抗原，会启动 Th1 免疫反应，并通过 CD4+ T 细胞背景下的抗原呈递细胞 (APC) 上的 HLA II 类发生抗原呈递。随后，CD4+ T 细胞和 APC 被募集至肺部、增殖、产生细胞因子和趋化因子，并最终形成肉芽肿。在 CBD 和 BeS 中发现第 69 位氨基酸 (E69) 具有谷氨酸的 HLA-DPB1 等位基因的患病率增加。在高达 40% 没有 BeS 或 CBD 的暴露于 Be 的工人中可能会发现同样的多态性，这表明其他易感性除了暴露之外，基因调控的因素或形式在疾病发病机制中也很重要。其他免疫介导疾病的越来越多数据表明，表观遗传机制与遗传易感性和环境相结合可能有助于解释疾病风险。表观遗传修饰通过 FOXP3 等关键基因的 DNA 甲基化和组蛋白修饰来决定 Th1 与 Th2 免疫反应，从而影响健康和疾病。迄今为止，尚未在环境诱发的肉芽肿性疾病中探索表观遗传改变。我们的初步数据表明，与 BeS 相比，CBD 中暴露和疾病部位（肺部）的关键免疫反应基因和网络存在显着的全基因组 DNA 甲基化差异。基于这些信息，该提案的总体假设是表观遗传机制影响基因表达和免疫细胞分化，最终影响肉芽肿性肺病的风险。使用整合的基因组方法，我们将首先在 CBD、BeS 和正常对照的病例对照研究中定义 CD4+ 肺细胞的表观遗传改变（全基因组甲基化），无论是否接触铍。随后，我们将确定影响基因转录的功能甲基化改变，这些信息将扩大我们对 CBD 发病机制的理解。由于去甲基化剂，如 5-氮杂胞苷 (AZA) 和地西他滨目前用于治疗免疫介导的疾病，我们将评估通过去甲基化 (AZA) 或去甲基化 (AZA) 治疗 CBD、BeS 和对照 CD4+ 肺细胞的经过验证的甲基化和基因表达靶点的变化。甲基化剂（叶酸）。这项研究将提供与此类药物作为治疗靶点相关的数据。此外，随着我​​们对表观基因组的了解不断加深，从该提案中获得的信息将有助于揭示其他与暴露相关的非传染性肉芽肿性疾病的发病机制，以及基因组暴露关系。