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：
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
项目类别：
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&apos 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

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 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，并涉及该问题。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。在发育或疾病进展的不同阶段都很重要，我们重点关注 T 细胞固有的和 T 细胞。雄激素受体 (AR) 的细胞外在作用以及微生物群对 T1D 的影响机制鉴于问题的复杂性，我们计划实现几个精心选择的目标。继续为这一重要领域的研究的未来扩展奠定基础。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 T1D 的二态性。 1.1. 确定所有参与 AR 介导的 T1D 保护的细胞是否都是骨髓来源的； 1.2. 定义骨髓细胞在男性预防 T1D 中的作用； 1.3. 测试骨髓细胞在T细胞转移实验中的贡献； 1.4. 测试转录因子 AIRE 在 T1D 性二态性中的作用。具体目标 2. 研究 AR 信号传导对 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对曲目选择的影响； 2.3. 研究AR在调节与自身免疫相关的干扰素γ（IFNg）中的作用； 2.4. 研究AR在IFNg位点调节中的作用；具体目标 3. 确定微生物群在何时何地放大 AR 对 T1D 发展的影响。 3.1. 测试有条件 AR 缺陷的 GF 动物的 T1D 发展情况； 3.2. 确定微生物在其发育过程中是否会导致免疫细胞特性的变化； 3.3. 确定微生物群对男性产生抗 T1D 影响的时间表； 3.4. 确定哪些免疫相关途径受到微生物群的影响。