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: 9197647
• 负责人: LISA A MAIER
• 金额: $ 44.85万
• 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/9197647
• 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; FOXP3 gene; Folic Acid; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Transcription; Genome; Genomic approach; Genomics; Glutamic Acid; Goals; Granuloma; Granulomatous; HLA-DPB1 gene; Health; Heritability; Histones; Immune; Immune Response Genes; Immune response; Immunophenotyping; Individual; Inherited; Life; Light; Lung; Lung diseases; Mediating; Methylation; Modification; Organ; Pathogenesis; Pathogenicity; Pathway interactions; Positioning Attribute; Predisposition; Prevalence; Proliferating; Recruitment Activity; Regulation; Risk; Risk Factors; Sampling; Site; T-Lymphocyte; Testing; Viral Tumor Antigens; base; chemokine; clinical care; cytokine; disorder risk; epigenetic regulation; epigenome; epigenomics; genome wide association study; genome wide methylation; genome-wide; histone modification; human subject; non-smoker; peripheral blood; potential biomarker; 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）：本研究的目的是定义导致肉芽肿性肺病慢性铍病（CBD）的环境诱导表观遗传标记及其对基因表达的影响。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。本研究将确定CBD的致病途径和危险因素，该疾病的前体（铍致敏；BeS）和类似的环境诱导疾病。在遗传易感宿主的环境下，暴露于吸入的Be抗原，启动Th1免疫应答，在CD4+ T细胞的背景下，抗原呈递通过HLA II类在抗原呈递细胞（APC）上发生。随后，CD4+ T细胞和apc被募集到肺中增殖，产生细胞因子和趋化因子，最终形成肉芽肿。在CBD和BeS中发现具有69位谷氨酸（E69）的HLA-DPB1等位基因的患病率增加，这种多态性可能在高达40%的没有BeS或CBD的be暴露工人中发现，这表明除了暴露外，其他易感因素或遗传调控形式在疾病发病机制中也很重要。在其他免疫介导的疾病中，越来越多的数据表明，表观遗传机制与遗传易感性和环境的结合可能有助于解释疾病风险。表观遗传修饰通过DNA甲基化和关键基因（如FOXP3）的组蛋白修饰决定Th1对Th2的免疫反应，从而影响健康和疾病。迄今为止，还没有研究环境诱导的肉芽肿疾病的表观遗传改变。我们的初步数据表明，与BeS相比，CBD暴露和疾病部位（肺）的关键免疫反应基因和网络在全基因组DNA甲基化上存在显著差异。基于这些信息，该建议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，我们将首先定义CD4+肺细胞的表观遗传改变（全基因组甲基化），在CBD， BeS和正常对照的病例对照研究中，有和没有铍暴露。随后，我们将确定影响基因转录的功能性甲基化改变，这些信息将扩大我们对CBD发病机制的理解。由于去甲基化药物，如5-氮扎胞苷（AZA）和地西他滨（decitabine）目前被用于治疗免疫介导的疾病，我们将评估甲基化和基因表达靶点在治疗CBD、BeS和用去甲基化（AZA）或甲基化（叶酸）药物控制CD4+肺细胞中的变化。本研究将提供这类药物作为治疗靶点的相关数据。此外，随着我们对表观基因组的理解不断加深，从这一建议中获得的信息将揭示其他与暴露相关的非感染性肉芽肿疾病的发病机制，以及基因组与暴露的关系。