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）：这项研究的目的是定义环境引起的表观遗传标记及其对基因表达的影响，从而导致肉芽肿性肺部疾病，慢性铍病（CBD）。该研究依赖于我们独特合格的调查团队的专业知识和优势。这项研究将定义CBD的致病途径和危险因素，CBD是该疾病的先驱（铍敏化； BES）和类似的环境诱发疾病。在遗传易感宿主的情况下，接触吸入的是抗原，启动Th1免疫反应，在CD4+ T细胞的背景下，通过HLA II类抗原出现在抗原呈递细胞（APC）上。随后，将CD4+ T细胞和APC募集到肺部，增殖，产生细胞因子和趋化因子，并最终形成肉芽肿。在CBD中发现HLA-DPB1等位基因在氨基酸位置69（E69）的HLA-DPB1等位基因的患病率增加，并且在多达40％的无BES或CBD的裸露工人中，还可以发现同样的多态性，这表明其他遗传调节的其他易感因素或形式在遗传性疾病中必须在疾病疾病中也很重要，以使疾病的疾病疾病的疾病持losiseasic extosion extive extige extimention。其他免疫介导疾病中的数据不断增长，表明表观遗传机制与遗传易感性和环境结合使用可能有助于解释疾病的风险。表观遗传修饰通过DNA甲基化和关键基因（例如FOXP3）的组蛋白修饰确定了TH1与Th2免疫反应，从而影响了健康和疾病。迄今为止，在环境引起的肉芽肿性疾病中尚未探索表观遗传改变。我们的初步数据表明，与BES相比，CBD的暴露和疾病部位的关键免疫反应基因和网络中关键免疫反应基因和网络的明显显着的DNA甲基化差异。基于此信息，该提案的总体假设是表观遗传机制会影响基因表达和免疫细胞分化，最终影响肉芽肿性肺部疾病的风险。使用综合基因组方法，我们将首先定义CD4+肺细胞中的表观遗传学改变（基因组宽甲基化），在CBD，BES和正常对照的案例控制研究中，有无铍暴露。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发病机理的理解。由于目前正在使用脱甲基化剂，例如5-偶氮丁胺（AZA）和德甲他滨（Decitabine）治疗免疫介导的疾病，因此我们将评估用脱甲基+肺甲基化（AZA）或甲基化（AZA）或甲基化（folication Acid）的剂量治疗CBD的验证甲基化和基因表达靶标的变化。这项研究将提供与这类药物相关的数据作为治疗的靶标。此外，从该提案中获得的信息将阐明其他相关的无感染性肉芽肿性疾病的发病机理，以及我们对表观基因组的理解的增长，对基因组暴露关系。