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: 10216963
• 负责人: ALEXANDER V CHERVONSKY
• 金额: $ 54.6万
• 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 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216963
• 关键词: Address; Androgen Receptor; Androgens; Animals; Area; Autoimmune; Autoimmune Diseases; 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; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Time; Untranslated RNA; base; commensal microbes; experimental study; germ free condition; hormone regulation; host microbiota; interest; macrophage; male; microbial; microbiota; microorganism; promoter; response; role model; sex; sexual dimorphism; systemic autoimmunity; 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。全身性狼疮红斑（SLE）， 硬皮病，多发性硬化症，Sjogren综合征和某些形式的1型糖尿病（T1D）是主要的 发生在女性中。它归因于多种因素，包括表达的基因 性别染色体，基因表达的激素调节，以及最近通过共生调节 微生物群。这是对疾病的性二态性的理解，要求解决问题 不同策略的结合。在此提案中，我们利用了执行状态的能力 使用普遍修改和gnotobiotic动物与原始和不断发展的艺术实验 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。我们提出了一种自身免疫性的“双重信号”模型，涉及微生物和 性激素。彼此之间，荷尔蒙和微生物影响不一定很简单：它们可能是 在发育或疾病进展的不同阶段很重要。我们已经确定了许多基因 由马酮（雄激素）受体调节，现在可以阐明 这种法规和自身免疫性。鉴于问题的复杂性，我们计划仔细追求几个 选定的目标将为这一重要领域的研究未来扩展奠定基础。 AIM 1：测试自身免疫性性二态性的微生物受累的双重信号模型。 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。 通过激素独立于微生物群。 AIM 2：阐明涉及免疫激素调节的特定机制 我们将研究Horsene和IFNγ产生的微生物调节的机制：我们将测试 长长的非编码RNA称为巢的假说控制IFNγ产生的性别偏见，并测试 它与1型糖尿病（T1D）中的性别偏见有关。 我们将研究性激素在调节性磷酸酶PTPN22及其表达的贡献中的作用 在T1D中的作用。 AIM 3：微生物群在系统性自身免疫性的性二态性中的作用 为了确定微生物群在性二态性中的作用有多一般，我们将测试一种系统性的模型 自身免疫性具有良好的性二态性-b6.nzm小鼠 - 在SPF和GF条件下。 我们将确定由雄激素调节的模型基因的作用（Nest和Ptpn22），我们将操纵 启动子中的马龙响应元素，并测试全身性红斑狼疮的后果 （SLE）。