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: 10608647
• 负责人: ALEXANDER V CHERVONSKY
• 金额: $ 66.32万
• 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 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608647
• 关键词: Address; Adopted; Adverse reactions; Affect; Androgen Receptor; Animals; Antigens; Area; Attenuated; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bone Marrow; Breeding; Cells; Computing Methodologies; Data; Development; Disease; Disease Progression; Environmental Risk Factor; Evolution; Female; Fetus; Foundations; Future; Gene Expression; Gene Expression Regulation; Genetic Drift; Genetic Models; Germ-Free; Gnotobiotic; Goals; Gonadal Steroid Hormones; Hormonal; Hormones; Immune; Immune signaling; Immune system; Infection; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Mediating; Microbe; Modeling; Molecular; Mothers; Multiple Sclerosis; Mus; Myeloid Cells; Non obese; Organism; Pathway interactions; Phosphoric Monoester Hydrolases; Play; Pregnancy; Prevalence; Process; Property; Receptor Signaling; Regulation; Research; Resistance; Role; Scleroderma; Sex Bias; Sex Chromosomes; Signal Transduction; Sjogren' s Syndrome; Systemic Lupus Erythematosus; Systems Development; T-Lymphocyte; T-cell receptor repertoire; Testing; Thymus Gland; Time; Vaccination; cell type; commensal microbes; diabetic; experimental study; feeding; flexibility; hormone regulation; imprint; male; microbial; microbiota; microorganism; prevent; sex; sexual dimorphism; timeline; transcription factor

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 are focusing on T cell-intrinsic and T- cell-extrinsic effects of Androgen Receptor (AR) and the mechanisms of microbiota’s effect on T1D development. Given the complexity of the problem, we plan to pursue several carefully selected goals that will continue to lay foundation for the future expansion of research in this important area. Specific Aim 1. Determine the input of T cell-intrinsic and T cell-extrinsic mechanisms in the sexual dimorphism of T1D. 1.1. Determine whether all cells involved in AR-mediated protection from T1D are of bone marrow origin; 1.2. Define the role of myeloid cells in male protection from T1D; 1.3. Test the contribution of myeloid cells in T cell transfer experiments; 1.4. Test a role that transcription factor AIRE plays in sexual dimorphism of T1D. Specific Aim 2. Investigate the influence of AR signaling on T cell selection and function 2.1. Determine the influence of AR on the TCR repertoires; 2.2. Determine how the properties of the TCR affect the influence of AR on repertoire selection; 2.3. Study the role of AR in regulation of interferon gamma (IFNg) related to autoimmunity; 2.4. Study the role of AR in regulation of the IFNg locus; Specific Aim 3. Determine where and when the microbiota amplifies AR effects on T1D development. 3.1. Test T1D development in GF animals with conditional AR deficiencies; 3.2. Determine whether microbes contribute to changes in immune cells properties during their development; 3.3. Establish the timeline to imprinting males to become resistant to T1D by the microbiota; 3.4. Determine which immune-related pathways are affected by the microbiota.

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。我们专注于T细胞内在和T- 雄激素受体（AR）的细胞外效应及微生物群对T1 D的作用机制 发展鉴于问题的复杂性，我们计划追求几个精心挑选的目标， 继续为今后扩大这一重要领域的研究奠定基础。 具体目标1.确定T细胞-内在和T细胞-外在机制在性行为中的输入 T1 D的二型性。 1.1.确定是否所有参与AR介导的T1 D保护的细胞都是骨髓来源的; 1.2.明确骨髓细胞在男性T1 D保护中的作用; 1.3.检测髓系细胞在T细胞转移实验中的贡献; 1.4.测试转录因子AIRE在T1 D性二型性中的作用。 具体目标2。研究AR信号对T细胞选择和功能的影响 2.1.确定AR对TCR库的影响; 2.2.确定TCR的特性如何影响AR对库选择的影响; 2.3.研究AR在自身免疫相关干扰素γ（IFNg）调节中的作用; 2.4.研究AR在IFNg基因座调节中的作用; 具体目标3。确定微生物群在何处以及何时放大AR对T1 D发展的影响。 3.1.在具有条件性AR缺陷的GF动物中测试T1 D发展; 3.2.确定微生物是否有助于免疫细胞在发育过程中的特性变化; 3.3.建立时间轴，通过微生物群使男性对T1 D产生抗性; 3.4.确定哪些免疫相关途径受到微生物群的影响。