Gene Regulation as a Foundation for Autoimmune Disease Prevention

基因调控作为自身免疫性疾病预防的基础

• 批准号: 10172832
• 负责人: Matthew Tyson Weirauch
• 金额: $ 96.37万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172832
• 关键词: Address; Alleles; Antibodies; Autoimmune; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Binding Sites; Celiac Disease; Cell Line; ChIP-seq; Chromatin; Chromosome Mapping; Chronic Childhood Arthritis; Complex; Crohn' s disease; DNA; DNA Binding; DNA Sequence; Data; Data Set; Disease; Enhancers; Environment; Epstein-Barr Virus Infections; Epstein-Barr Virus Nuclear Antigens; Etiology; Evaluation; Foundations; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Risk; Genome; Genomics; Genotype; Goals; Human; Human Herpesvirus 4; Immune; Individual; Inflammatory Bowel Diseases; Informatics; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Intervention; Knowledge; Ligands; Luciferases; MicroRNAs; Modeling; Multiple Sclerosis; Nucleic Acid Binding; Pathogenesis; Pathway interactions; Predisposition; Prevention; Prevention strategy; Preventive; Procedures; RNA; RNA Binding; RNA-Binding Proteins; Reagent; Regulator Genes; Relative Risks; Research Design; Rheumatoid Arthritis; Role; System; Systemic Lupus Erythematosus; Testing; Therapeutic; Therapy Evaluation; Ulcerative Colitis; Untranslated RNA; Variant; Virus; base; causal variant; cell type; chromatin immunoprecipitation; cooperative study; data repository; data resource; design; disorder prevention; disorder risk; experimental study; genetic variant; genome wide association study; genome-wide; genome-wide analysis; human DNA; infected B cell; insight; large datasets; member; next generation sequencing; novel strategies; prevent; preventive intervention; programs; risk variant; transcription factor

ABSTRACT. We propose a Cooperative Study Group for the Autoimmune Disease Prevention initiative that will “contribute knowledge critical to achieving the goal of designing and administering practical interventions to prevent one or more autoimmune diseases” (quotes are from RFA-AI-16-003). Our proposal is to define “the role of genetic susceptibility and environmental influences in autoimmune disease”, to “determine the mechanisms by which defined genetic risk alleles influence susceptibility to autoimmune disease”, and to facilitate the “identification and elucidation of cellular and immune pathways that may provide targets for preventive interventions”. Preliminary data show sets of ~25 transcription factors and co-factors (TFs) that immunoprecipitate DNA sequences (ChIP-seq) at disease risk loci producing powerful associations (2.7≤Relative Risk≤40, 1.5E- 06≥pc≥4.6E-53) for each of 7 autoimmune diseases: multiple sclerosis (MS), type 1 diabetes (T1D), rheumatoid arthritis (RA), Inflammatory bowel disease (IBD), juvenile idiopathic arthritis (JIA), celiac disease (CelD), and systemic lupus erythematosus (SLE). These TFs prominently include one that is encoded by a virus, Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2), and nearly half of the associated TFs are known to be components of EBV associated super-enhancers. While the new results are compelling; the underlying data are currently incomplete and generally inadequate for technical and study design issues; nevertheless, we have identified several convincing examples of allele-dependent differences in TF binding to plausible causal variants from disease risk loci (e.g., at IL-10, CD37, and TMBIM1). These illustrate the nomination of specific molecular interactions for possible contributions to the consequent autoimmune disease; in addition, they provide powerful guidance for the data that should be developed in order to understand the interaction of environment (here EBNA2) with risk loci to produce autoimmune disease mechanisms. We propose 4 aims: We will test the association of nucleic acid binding by regulatory molecules (TFs, microRNAs, long non-coding RNAs, and RNA binding proteins) with autoimmune disease loci (Aim 1); we will generate experimental regulatory molecule binding data to reveal possible disease generating mechanisms (Aim 2); we will test specific hypotheses of gene regulation ex vivo and localize gene regulatory effects to individual variants with chromatin edited cell lines (Aim 3); and we will extend our new approach to our Autoimmune Prevention Study Group colleagues and their projects, as “alpha testers” of our informatics and experimental approaches, in order to advance our basic understanding of autoimmunity as rapidly as possible (Aim 4). Overall, this project will provide pathophysiological mechanisms for autoimmune diseases, will couple the causal genes to environment for at least the example of EBV, will demonstrate how a much larger data resource could provide transforming insights into many diseases, and will generate ex vivo models that will provide reagents and data to facilitate the subsequent evaluation of therapies and preventive strategies.

抽象的。 我们提议成立一个自身免疫性疾病预防合作研究小组，该倡议将“有助于 对于实现设计和管理实际干预措施以预防一种或多种疾病的目标至关重要的知识 更多自身免疫性疾病”（引自 RFA-AI-16-003）我们的建议是定义“遗传的作用”。 自身免疫性疾病的易感性和环境影响”，“确定自身免疫性疾病的机制” 确定的遗传风险等位基因影响自身免疫性疾病的易感性”，并促进“识别 并阐明可能为预防性干预提供目标的细胞和免疫途径。” 初步数据显示约 25 个转录因子和辅助因子 (TF) 可以免疫沉淀 DNA 疾病风险位点的序列 (ChIP-seq) 产生强大的关联 (2.7≤相对风险≤40, 1.5E- 06≥pc≥4.6E-53) 对于 7 种自身免疫性疾病：多发性硬化症 (MS)、1 型糖尿病 (T1D)、 类风湿性关节炎 (RA)、炎症性肠病 (IBD)、幼年特发性关节炎 (JIA)、乳糜泻 疾病 (CelD) 和系统性红斑狼疮 (SLE) 这些 TF 主要包括以下一项： 由病毒、EB 病毒 (EBV) 核抗原 2 (EBNA2) 和近一半的相关蛋白编码 众所周知，转录因子是 EBV 相关超级增强子的组成部分，而新的结果令人信服。 基础数据目前不完整，通常不足以解决技术和研究设计问题； 尽管如此，我们已经确定了几个令人信服的例子，说明 TF 结合的等位基因依赖性差异。 来自疾病风险位点（例如，IL-10、CD37 和 TMBIM1）的可能因果变异。 提名可能对随后的自身免疫性疾病产生影响的特定分子相互作用； 此外，它们还为应开发的数据提供了强有力的指导，以了解 环境（此处为 EBNA2）与风险位点的相互作用产生自身免疫性疾病机制。 我们提出 4 个目标： 我们将测试调节分子（TF、 具有自身免疫性疾病位点的 microRNA、长非编码 RNA 和 RNA 结合蛋白（目标 1）； 生成实验性调节分子结合数据，以揭示可能的疾病发生机制（目标 2）；我们将离体测试基因调控的具体假设，并将基因调控效应定位于个体 染色质编辑细胞系的变体（目标 3）；我们将把我们的新方法扩展到自身免疫领域； 预防研究小组的同事和他们的项目，作为我们信息学和实验的“阿尔法测试者” 方法，以尽快增进我们对自身免疫的基本了解（目标 4）。 该项目将提供自身免疫性疾病的病理生理机制，将致病基因耦合起来 至少以 EBV 为例，将展示更大的数据资源如何提供 转变对许多疾病的认识，并将生成提供试剂和数据的离体模型 促进后续治疗和预防策略的评估。

项目成果

Xenobiotic and endobiotic handling by the mucosal immune system.

粘膜免疫系统的异生素和内生素处理。

• 发表时间: 2018-11
• 影响因子: 2.5
• 作者: Chen, Mei Lan;Sundrud, Mark S
• 通讯作者: Sundrud, Mark S

Emerging roles of bile acids in mucosal immunity and inflammation.

胆汁酸在粘膜免疫和炎症中的新作用。

• 发表时间: 2019-07
• 影响因子: 8
• 作者: Chen, Mei Lan;Takeda, Kiyoshi;Sundrud, Mark S
• 通讯作者: Sundrud, Mark S

The transcription factor CREM drives an inflammatory phenotype of T cells in oligoarticular juvenile idiopathic arthritis.

转录因子 CREM 驱动少关节型幼年特发性关节炎 T 细胞的炎症表型。

• 发表时间: 2018-06-20
• 作者: Ohl, Kim;Nickel, Helge;Moncrieffe, Halima;Klemm, Patricia;Scheufen, Anja;Föll, Dirk;Wixler, Viktor;Schippers, Angela;Wagner, Norbert;Wedderburn, Lucy R;Tenbrock, Klaus
• 通讯作者: Tenbrock, Klaus

Strong viral associations with SLE among Filipinos.

菲律宾人中病毒与系统性红斑狼疮密切相关。

• 发表时间: 2017
• 影响因子: 3.9
• 作者: Vista, Evan S;Weisman, Michael H;Ishimori, Mariko L;Chen, Hua;Bourn, Rebecka L;Bruner, Ben F;Hamijoyo, Laniyati;Tanangunan, Robelle D;Gal, Noga J;Robertson, Julie M;Harley, John B;Guthridge, Joel M;Navarra, Sandra V;James, Judith A
• 通讯作者: James, Judith A

S100A12 Is Associated with Response to Therapy in Juvenile Idiopathic Arthritis.

S100A12 与幼年特发性关节炎的治疗反应相关。

• 发表时间: 2018
• 作者: Gohar, Faekah;Anink, Janneke;Moncrieffe, Halima;Van Suijlekom;Prince, Femke H M;van Rossum, Marion A J;Dolman, Koert M;Hoppenreijs, Esther P A H;Ten Cate, Rebecca;Ursu, Simona;Wedderburn, Lucy R;Horneff, Gerd;Frosch, Michael
• 通讯作者: Frosch, Michael