Host's and microbiota's contribution to sexual dimorphism of autoimmunity

宿主和微生物群对自身免疫性二态性的贡献

• 批准号: 9388410
• 负责人: ALEXANDER V CHERVONSKY
• 金额: $ 55.2万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-16 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9388410
• 关键词: Address; Androgen Receptor; Androgens; Animals; Area; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bioinformatics; Cells; Chromatin; Complex; Computing Methodologies; Data; Data Analyses; Development; Disease; Disease Progression; Elements; Female; Foundations; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Germ-Free; Gnotobiotic; Goals; Gonadal Steroid Hormones; Hematopoietic; Hormonal; Hormone Responsive; Hormones; Human; Immunity; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Linear Models; Methods; Microbe; Modeling; Molecular; Multiple Sclerosis; Mus; Nature; Outcome; Phenotype; Phosphoric Monoester Hydrolases; Play; Production; Regulation; Research; Rodent; Role; Scleroderma; Sex Bias; Sex Chromosomes; Signal Transduction; Sjogren' s Syndrome; Solid; Symbiosis; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Time; Untranslated RNA; base; experimental study; germ free condition; hormone regulation; interest; macrophage; male; microbial; microbiota; microorganism; promoter; response; role model; sex; sexual dimorphism; thymocyte

Many of major autoimmune diseases are sexually dimorphic. Systemic Lupus Erythematosus (SLE), scleroderma, multiple sclerosis, Sjogren's syndrome, and some forms of Type 1 diabetes (T1D) are primarily occurring in females. It has been attributed to multiple factors including expression of the genes encoded by sex chromosomes, hormonal regulation of gene expression, and lately to unexpected regulation by commensal microbiota. Thus, understanding of sexual dimorphism of diseases requires that the problem be approached by a combination of different strategies. In this proposal, we take advantage of our abilities to perform state of the art experiments using genetically modified and gnotobiotic animals with original and constantly developing computational methods. Our preliminary data demonstrates the efficiency of such an integrative approach to the problem. We have suggested a `dual signal' model of autoimmunity involving regulation by microbes and sex hormones. Accordingly, hormonal and microbial influences do not have to be simultaneous: they may be important at different stages of development or disease progression. We already identified a number of genes that are regulated by hormone (androgen) receptors and are now posed to elucidate the connection between such regulation and autoimmunity. Given the complexity of the problem, we plan to pursue several carefully selected goals that will lay foundation for the future expansion of research in this important area. Aim 1: Test the dual signal model of microbial involvement in sexual dimorphism of autoimmunity. We will test whether gene expression patterns and chromatin status in T cells and macrophages are regulated by hormones independently of the microbiota. Aim 2: Elucidate specific mechanisms involved in hormonal regulation of immunity We will study the mechanisms of hormone and microbe-dependent regulation of IFNγ production: we will test the hypothesis that a long non-coding RNA termed NeST controls the gender bias of IFNγ production, and test its relevance to the gender bias in Type 1 Diabetes (T1D). We will study the role of sex hormones in contribution to expression of regulatory phosphatase Ptpn22 and its role in T1D. Aim 3: The role of microbiota in sexual dimorphism of systemic autoimmunity To determine how general the role of microbiota is in sexual dimorphism, we will test a model of systemic autoimmunity with well-established sexual dimorphism -B6.NZM mice- in SPF and GF conditions. We will determine a role of model genes regulated by androgens (NeST and Ptpn22) we will manipulate hormone-responsive elements in their promoters and test the consequences in Systemic Lupus Erythematosus (SLE).

许多主要的自身免疫性疾病是性二态性的。系统性红斑狼疮（SLE）， 硬皮病、多发性硬化、干燥综合征和某些形式的1型糖尿病（T1 D）主要是 发生在女性身上。它已被归因于多种因素，包括表达的基因编码的 性染色体，基因表达的激素调节，以及最近的意想不到的调节， 微生物群因此，理解疾病的性二态性需要通过以下方法来解决这个问题： 不同策略的组合。在这个建议中，我们利用我们的能力来执行国家的 艺术实验使用转基因和gnotobiotic动物与原始和不断发展 计算方法我们的初步数据证明了这种综合方法的效率， 问题所在我们已经提出了一种自身免疫的“双重信号”模型，涉及微生物的调节， 性激素因此，激素和微生物的影响不一定是同时发生的：它们可能是 重要的是在不同的发展阶段或疾病进展。我们已经确定了许多基因 受激素（雄激素）受体调节，现在被用来阐明 这种调节和自身免疫。鉴于问题的复杂性，我们计划仔细研究几个问题， 这些目标将为今后扩大这一重要领域的研究奠定基础。 目的1：检验微生物参与自身免疫性二型性的双信号模型。 我们将测试T细胞和巨噬细胞中的基因表达模式和染色质状态是否受到调节 由激素独立于微生物群。 目的2：阐明免疫激素调节的具体机制 我们将研究IFNγ产生的激素和微生物依赖性调节机制：我们将测试 一种称为NeST的长的非编码RNA控制IFNγ产生的性别偏倚的假设， 它与1型糖尿病（T1 D）的性别偏见的相关性。 我们将研究性激素在调节性磷酸酶Ptpn 22表达中的作用， 在T1 D中的作用 目的3：微生物群在系统性自身免疫性二型性中的作用 为了确定微生物群在两性异形中的作用有多普遍，我们将测试一个系统性的微生物群模型。 在SPF和GF条件下，具有明确的性二型性的自身免疫-B6.NZM小鼠。 我们将确定由雄激素调节的模型基因（NeST和Ptpn 22）的作用，我们将操纵 在其启动子中激活应答元件并测试系统性红斑狼疮的后果 （SLE）。