Commensal microbes and sexual dimorphism in autoimmunity

自身免疫中的共生微生物和性别二态性

• 批准号: 8828075
• 负责人: ALEXANDER V CHERVONSKY
• 金额: $ 23.14万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828075
• 关键词: Accounting; Address; Adult; Affect; Animal Model; Antibiotic Therapy; Autoimmune Diseases; Autoimmunity; Chicago; Complex; Data; Dependence; Development; Diabetes Mellitus; Disease; Disease Progression; Environment; Female; Gender; Gene Expression; Gene Expression Profiling; Genetic Variation; Germ-Free; Gnotobiotic; Gonadal Steroid Hormones; Health; Hormonal; Hormones; Human; Immunity; Inbred NOD Mice; Incidence; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Knowledge; Lead; Metabolism; Microbe; Minor; Modeling; Multiple Sclerosis; Mus; Mutation; Procedures; Production; Publications; Publishing; Regulation; Reporting; Research; Resistance; Role; Scleroderma; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Sterility; Surveys; System; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Testosterone; The Jackson Laboratory; Thyroid Gland; Time; Uncertainty; Universities; Work; antimicrobial; cell type; commensal microbes; genetic approach; macrophage; male; microbial; mouse model; repository; sexual dimorphism

DESCRIPTION (provided by applicant): Many of major autoimmune diseases are sexually dimorphic. Systemic Lupus Erythematosus (SLE), scleroderma, multiple sclerosis, Sjogren's syndrome, autoimmune diseases of thyroid gland and others are primarily occurring in females. In a mouse model of spontaneous type 1 diabetes (T1D in non-obese diabetic, NOD, mice) the disease is stronger in females. A survey of NOD colonies around the world found that not only overall incidence of T1D varied greatly between different facilities, but that the female/male incidence ratio varied. The variability suggests that some factors that cannot be easily accounted for clearly affect the disease progression. In other facilities, including ours, the incidence in males is even lower (about 15-20% at 30 wks), whereas the incidence in females is around 65-80%. As a part of the studies of the role of microbial environment on T1D development, we have rederived NOD mice into germ-free (sterile) conditions. We realized that these mice no longer showed sexual dimorphism! That means that the hormones (clearly shown to be involved) and the microbiota are interacting in some way that affects the disease progression. Our main hypothesis suggests that the hormones and microbial products act together (dual-signal hypothesis) to induce tolerance to T1D in males. Preliminary analysis has revealed a role for Interferon-gamma in protection of males from T1D. It is proposed to test the hypothesis by a variety of approaches including colonization of germ-free mice with defined microbiota, genetic approach and gene expression analysis. We will also to test whether systemic immunity in a common genetically complex mouse model of SLE is also sexually dimorphic because of the presence of microbes. Accordingly, two specific aims are: Specific Aim 1. Investigate the effector mechanisms that make NOD males more resistant to T1D. We will test the role of specific microbial lineages in controlling sexual dimorphism; we will study te signaling pathway and cell types involved in tolerance induction using gene-expression and genetic approaches. We will study how manipulations of sex hormones affect microbial composition and functions; we will use gene expression analysis to delineate signaling pathways important for hormone-dependent control over microbiota. Specific Aim 3. Investigate whether sexual dimorphism in a mouse model of SLE is dependent on microbes. We will study the role of microbiota in induction and sexual dimorphism in NZBWF1 mice in germ-free environment.

描述（由申请人提供）：许多主要自身免疫性疾病是性别二态性的。系统性红斑狼疮（SLE）、硬皮病、多发性硬化症、干燥综合征、甲状腺自身免疫性疾病等主要发生于女性。在自发性 1 型糖尿病（非肥胖糖尿病小鼠中的 T1D，NOD，小鼠）的小鼠模型中，这种疾病在雌性中更为严重。对世界各地 NOD 群体的一项调查发现，不仅不同机构之间 T1D 的总体发病率差异很大，而且女性/男性的发病率也不同。这种变异性表明，一些不易解释的因素明显影响疾病进展。在包括我们在内的其他机构中，男性的发病率甚至更低（30 周时约为 15-20%），而女性的发病率约为 65-80%。作为微生物环境对 T1D 发展的作用研究的一部分，我们将 NOD 小鼠重新移植到无菌（无菌）条件下。我们意识到这些小鼠不再表现出性别二态性！这意味着激素（明确显示参与其中）和微生物群以某种方式相互作用，从而影响疾病的进展。我们的主要假设表明，激素和微生物产物共同作用（双信号假说）来诱导男性对 T1D 的耐受性。初步分析揭示了干扰素-γ 在保护男性免受 T1D 感染方面的作用。建议通过多种方法来检验这一假设，包括对具有明确微生物群的无菌小鼠进行定植、遗传方法和基因表达分析。我们还将测试常见的遗传复杂的系统性红斑狼疮小鼠模型的全身免疫是否也因微生物的存在而呈现性别二态性。因此，有两个具体目标： 具体目标 1. 研究使 NOD 男性对 T1D 更具抵抗力的效应机制。我们将测试特定微生物谱系在控制性别二态性方面的作用；我们将使用基因表达和遗传方法研究参与耐受诱导的信号通路和细胞类型。我们将研究性激素的操纵如何影响微生物的组成和功能；我们将使用基因表达分析来描绘对于激素依赖性微生物群控制至关重要的信号通路。具体目标 3. 研究 SLE 小鼠模型的性别二态性是否依赖于微生物。我们将研究微生物群在无菌环境中 NZBWF1 小鼠诱导和性别二态性中的作用。