Impact of Pathogenic and Protective Environmental Exposures on Autoimmune Disease

致病性和保护性环境暴露对自身免疫性疾病的影响

• 批准号: 8970378
• 负责人: DIANE L KAMEN
• 金额: $ 16.45万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-10 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970378
• 关键词: Accounting; Address; Affect; African American; Age; Autoantibodies; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Biological Markers; Blood; Chronic; Clinical; Communities; DNA; Data; Development; Diagnosis; Diet; Disease; Environment; Environmental Exposure; Environmental Pollution; Environmental Risk Factor; Epitopes; Equilibrium; Etiology; Feces; First Degree Relative; Food; Frequencies; Funding; Future; Generations; Genes; Genetic Predisposition to Disease; Genomics; Genotype; Grant; Heavy Metals; Hour; Immune; Immunologics; Incidence; Individual; Inflammatory; Intervention; Metagenomics; Microbe; Modeling; Modification; Organ; Participant; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Population; Prevalence; Production; Questionnaires; Research; Risk Factors; Role; Sampling; Severities; Smoking; Specificity; Structure; Susceptibility Gene; Systemic Lupus Erythematosus; Talents; Testing; Trust; United States National Institutes of Health; Variant; Whole-Genome Shotgun Sequencing; Woman; Work; cost; genetic variant; gut microbiota; high throughput analysis; metagenome; microbial; microbial community; microbiome; pollutant; pre-clinical; public health relevance; risk variant; sex; trait; young woman

 DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a chronic and potentially severe autoimmune disease which disproportionately affects women and African Americans (AA). Despite the role of environmental factors in modulating autoimmunity pathogenesis, the specific mechanisms by which it acts remain poorly understood. A growing body of evidence implicates the gut microbiota in the development of autoimmune disorders. In this study we will characterize the microbial composition (microbiome) and gene content (metagenome) of fecal DNA from samples obtained from AA patients with SLE, their unaffected first-degree relatives who show signs of autoimmunity, and healthy, unrelated, autoantibody-negative AA controls. The overall hypothesis of this proposal is that there is gut microbial variation at both the structural and functional level between individuals that influences development of autoimmunity and autoimmune disease. We will test this hypothesis by accomplishing 3 Specific Aims: 1) Testing the hypothesis that gut community structure (microbiome) correlates with markers of autoimmunity and SLE disease. 2) Testing the hypothesis that the microbiome's genes, variants and functional capabilities (metagenome) are associated with autoimmunity and SLE disease. 3) Testing the hypothesis that the gut microbial composition correlates with markers of autoimmunity and SLE disease in a multivariate model, taking into account host genotype data, phenotypic traits, diet and other exposures. Upon completion of these Aims we will have systematically identified bacterial biomarkers (e.g. SNPs, genes, strains) that correlate with SLE, can be investigated in other autoimmune diseases, and serve as potential targets for disease treatment.

 描述（由申请人提供）：系统性红斑狼疮 (SLE) 是一种慢性且可能严重的自身免疫性疾病，尤其影响女性和非裔美国人 (AA)。尽管环境因素在调节自身免疫发病机制中发挥着作用，但其作用的具体机制仍知之甚少。越来越多的证据表明肠道微生物群与自身免疫性疾病的发展有关。在这项研究中，我们将从患有 SLE 的 AA 患者、其未受影响的表现出自身免疫迹象的一级亲属以及健康、无关、自身抗体阴性的 AA 对照中获得的样本中，表征粪便 DNA 的微生物组成（微生物组）和基因内容（宏基因组）。该提案的总体假设是，个体之间的肠道微生物在结构和功能水平上都存在差异，影响自身免疫和自身免疫疾病的发展。我们将通过实现 3 个具体目标来检验这一假设：1) 检验肠道群落结构（微生物组）与自身免疫和 SLE 疾病标志物相关的假设。 2) 检验微生物组的基因、变异和功能（宏基因组）与自身免疫和 SLE 疾病相关的假设。 3) 在多变量模型中检验肠道微生物组成与自身免疫和 SLE 疾病标志物相关的假设，同时考虑宿主基因型数据、表型特征、饮食和其他暴露。完成这些目标后，我们将系统地鉴定与 SLE 相关的细菌生物标志物（例如 SNP、基因、菌株），可在其他自身免疫性疾病中进行研究，并作为疾病治疗的潜在靶标。