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Epigenetic Regulation of Immune Pathways in Sarcoidosis

结节病免疫途径的表观遗传调控

基本信息

批准号：
10200129
负责人：
LISA A MAIER
金额：
$ 69.76万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200129
关键词：
Affect Alleles Antigen Presentation Antigen-Presenting Cells Antigens Area Azacitidine Biological Biological Markers Blood Cells Bronchoalveolar Lavage CD4 Positive T Lymphocytes Case-Control Studies Cell Differentiation process Cells Cessation of life Chronic Cicatrix Critical Pathways DNA Methylation Data Decitabine Development Disease Disease remission Educational workshop Environment Environmental Exposure Epigenetic Process Evaluation Exposure to FOXP3 gene Folic Acid Future Gene Expression Genes Genetic Genetic Predisposition to Disease Genetic Transcription Genome Genomic approach Genomics Goals Granuloma Granulomatous HLA-DRB1 Health Heritability Immune Immune Response Genes Immune response Immunophenotyping Individual Inhalation Life Light Lung Lung diseases MAP Kinase Gene Mediating Methylation Modification Morbidity - disease rate National Heart, Lung, and Blood Institute Natural History Other Genetics Pathogenesis Pathogenicity Pathway interactions Phenotype Predisposition Prevalence Progressive Disease Proliferating Pulmonary Sarcoidosis Race Regulation Research Resolution Risk Risk Factors Sampling Sarcoidosis Signal Pathway Site T-Cell Receptor T-Lymphocyte Testing Underserved Population Validation Variant base chemokine cohort cytokine disease phenotype disorder risk epigenetic regulation genetic variant genome-wide histone modification human subject immunoregulation non-smoker novel potential biomarker programs public health relevance pyrosequencing recruit targeted treatment therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT The goal of this study is to define the epigenetic marks and their impact on gene expression that result in the granulomatous lung disease, sarcoidosis, and two of the most common sarcoidosis phenotypes, progressive pulmonary disease and remitting disease. The study relies on the expertise and strengths of our uniquely qualified investigative team. It will define pathogenic pathways and risk factors for sarcoidosis and two common phenotypes of disease, and have implications for similar immune mediated diseases. In sarcoidosis, it appears that exposure to an unknown inhaled 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 chemokines, and eventually form granulomas. An increased prevalence of HLA-DRB1 alleles is found in sarcoidosis, although the exact alleles vary based on an individual's race, ethnic background and disease phenotype. There are a limited number of other genetic variants associated with sarcoidosis, suggesting that other susceptibility factors or forms of genetic regulation must be important in disease pathogenesis. Growing data in other lung 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 sarcoidosis. 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 sarcoidosis compared to subjects without granulomatous lung disease. Based on this information, the overarching hypothesis for this proposal is that DNA methylation changes in genes in key immune pathways impact gene expression and immune cell differentiation, and thus risk of sarcoidosis. Using an integrated genomic approach we will first define epigenetic alterations in CD4+ lung cells, in a case control study of sarcoidosis cases with progressive and remitting disease and normal controls. Subsequently, we will determine functional methylation alterations that impact gene transcription, information which will expand our understanding of the pathogenesis of sarcoidosis. 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 sarcoidosis 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 sarcoidosis and its phenotypes and on genome-exposure relationships.

项目摘要/摘要这项研究的目标是定义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、结节病和两种最常见的进行性结节病表型肺部疾病和缓解性疾病。这项研究依赖于我们独特的合格的调查团队。它将定义结节病的致病途径和危险因素，以及两种常见的疾病的表型，并对类似的免疫介导性疾病有影响。在结节病中，它似乎在遗传易感宿主的环境中暴露于未知的吸入性抗原(S)，启动Th1 免疫应答，通过抗原提呈细胞(APC)上的HLAII类递呈发生关于CD4+T细胞的背景。随后，CD4+T细胞和APC被招募到肺中，增殖，产生细胞因子和趋化因子，最终形成肉芽肿。人类白细胞抗原-DRB1等位基因的增加是在结节病中发现，尽管确切的等位基因因个人的种族、民族背景和疾病表型。与结节病相关的其他遗传变异数量有限，这表明其他易感因素或遗传调节形式在疾病发病机制中肯定是重要的。其他肺部疾病的不断增长的数据表明，表观遗传机制与遗传易感性和环境可能有助于解释疾病风险。表观遗传修饰决定Th1与通过DNA甲基化和组蛋白修饰关键基因如FOXP3和从而影响健康和疾病。到目前为止，在结节病中还没有发现表观遗传学改变。我们的初步数据显示全基因组DNA甲基化在关键免疫反应中存在显著差异结节病患者暴露部位和疾病部位的基因和网络，即肺，与无肉芽肿性肺部疾病。根据这一信息，这一提议的首要假设是DNA 关键免疫通路基因甲基化变化影响基因表达和免疫细胞分化，因此有患结节病的风险。使用整合的基因组方法，我们将首先定义在进展性和非进展性结节病病例对照研究中，CD4+肺细胞的表观遗传学改变疾病缓解期和正常对照组。随后，我们将确定功能性甲基化改变影响基因转录的信息，将扩大我们对结节病发病机制的认识。作为去甲基剂，如5-氮胞苷(AZA)和地西他滨目前正被用于治疗免疫介导性疾病，我们将评估有效甲基化和基因表达靶点治疗的变化使用去甲基化(AZA)或甲基化(叶酸)制剂的结节病CD4+肺细胞。这项研究将提供与作为治疗目标的这类药物相关的数据。此外，从这项提案中获得的信息将阐明结节病的发病机制及其表型，以及基因组与暴露的关系。