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

基本信息

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
项目类别：
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&apos 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

项目摘要

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都是性别二态性的，系统性红斑狼疮（SLE）。硬皮病、多发性硬化症、干燥综合征和某些形式的 1 型糖尿病 (T1D) 主要是它发生在女性身上，归因于多种因素，包括编码基因的表达。性染色体、基因表达的激素调节以及最近共生体的意外调节因此，了解疾病的性别二态性需要通过以下方法来解决这个问题。在这个建议中，我们利用我们的能力来执行不同的策略。使用转基因和限生动物进行艺术实验，具有原创性和不断发展的特点我们的初步数据证明了这种综合方法的效率。我们提出了微生物调节自身免疫的“双信号”模型。因此，激素和微生物的影响不一定是同时发生的：它们可能是同时发生的。我们已经确定了许多基因在发育或疾病进展的不同阶段都很重要。受激素（雄激素）受体调节，现在被用来阐明之间的联系鉴于问题的复杂性，我们计划仔细研究几个。选定的目标将为这一重要领域的未来研究扩展奠定基础。目标 1：测试微生物参与自身免疫性二态性的双信号模型。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独立于微生物群的激素。目标 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：我们将测试假设名为 NeST 的长非编码 RNA 控制 IFNγ 产生的性别偏差，并进行了测试它与 1 型糖尿病 (T1D) 中的性别偏见相关。我们将研究性激素在调节性磷酸酶 Ptpn22 表达中的作用及其在 T1D 中的作用。目标 3：微生物群在系统性自身免疫性二态性中的作用为了确定微生物群在性别二态性中的作用有多普遍，我们将测试一个系统模型在 SPF 和 GF 条件下具有明确的性别二态性的自身免疫 -B6.NZM 小鼠。我们将确定雄激素（NeST 和 Ptpn22）调节的模型基因的作用，我们将操纵启动子中的激素反应元件并测试系统性红斑狼疮的后果（系统性红斑狼疮）。