Investigating cross-regulation of the microbiome and mucosal immune system using humanized mice

使用人源化小鼠研究微生物组和粘膜免疫系统的交叉调节

• 批准号: 9109630
• 负责人: Jeremy Allen Goettel
• 金额: $ 15.04万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109630
• 关键词: Address; Agonist; Area; Aryl Hydrocarbon Receptor; Bacteria; Boston; Chronic; Clinical Trials; Colitis; Colorectal Cancer; Communication; Communities; Complex; Crohn' s disease; Data; Defect; Development; Digestive System Disorders; Disease; Ecology; Experimental Models; Exposure to; FOXP3 gene; Functional disorder; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Germ-Free; Goals; Health; Hematopoietic stem cells; Homeostasis; Host Defense; Human; Human Microbiome; Hypersensitivity; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immune system; Immunobiology; Immunodeficient Mouse; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Life; Link; Manuscripts; Mediating; Mendelian disorder; Modeling; Molecular Abnormality; Mouse Strains; Mus; Mutate; Nature; Pathway interactions; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Physiological; Polysaccharides; Regulation; Regulatory T-Lymphocyte; Research; Risk; Rodent Model; Role; Stress; System; Taxon; Testing; Therapeutic; Time; Translating; Ulcerative Colitis; Variant; Volatile Fatty Acids; adaptive immunity; aryl hydrocarbon receptor ligand; clinically relevant; clinically significant; commensal microbes; genome wide association study; germ free condition; gut microbiome; human disease; humanized mouse; improved; in vivo; insight; medical schools; metabolome; microbial; microbial community; microbiome; microbiota; mouse model; novel; reconstitution; risk variant

 DESCRIPTION (provided by applicant): In the intestine, exposure to commensal microbes early in life is a key determinant in the development of mucosal immune tolerance and homeostasis. Dysfunction of tolerogenic and homeostatic immune pathways underlies a broad variety of chronic inflammatory disorders, including not just Crohn's disease and ulcerative colitis, but also allergy, and even colorectal cancer. The immune dysfunction associated with such disorders is complex and still incompletely understood, and further defining these mechanisms is of significant clinical relevance. In recent years the role of the microbiome in human health and disease has become an area of intense focus. Although sequence profiling of the human microbiome has characterized the microbial communities present at mucosal interfaces in health and disease, our understanding of the relationship between the human intestinal microbiome and human mucosal immune system remains incomplete. Genome-wide association studies have identified numerous polymorphisms that are associated with altered risk for inflammatory bowel disease (IBD), many of which are involved in host defense and may contribute to dysbiosis, a well-established hallmark of IBD. It is not known if dysbiosis is caused by these variants or is a result from underlying inflammation. Similarly, it is unknown whether alterations in the microbiome of IBD patients are sufficient to promote immune dysregulation. Experimental murine models have given some insight but disease signatures in murine models of inflammation often poorly correlate with human disease. Furthermore, it has been shown that development and maturation of the murine mucosal immune system requires host-specific gut microbiome necessitating novel experimental systems to investigate human immunobiology. My goal is to understand the cross-regulation between the human mucosal immune system and human microbiome. I have developed a novel humanized mouse strain that displays adaptive immune responses and can recapitulates a human immune disease when using HSCs with mutated FOXP3. I have re-derived this strain into germ-free conditions to permit defined colonization strategies to investigate human mucosal immune development/function and the dynamics of the human intestinal microbiome providing an opportunity to characterize the developing human mucosal immune system not previously achieved in experimental models. My hypothesis is that both genetic susceptibility and dysbiosis alter mucosal immune development and contributes to aberrant immune responses in the intestine and I will address this in three aims: 1) whether dysbiosis impacts human mucosal immune system 2) whether genetic susceptibility perturbs microbiome stability; 3) whether exogenous administration of microbial byproducts or metabolites potentiates human Treg development.

 描述（由适用提供）：在肠道中，生命早期对共生微生物的接触是粘膜免疫降低和稳态发展的关键。耐受性和稳态免疫病的功能障碍是各种各样的慢性炎症性疾病的基础，包括克罗恩病和溃疡性结肠炎，还过敏甚至结肠直肠癌。与此类疾病相关的免疫功能障碍是复杂的，但仍未完全理解，进一步定义这些机制具有显着的临床相关性。近年来，微生物组在人类健康和疾病中的作用已成为一个重点的领域。尽管人类微生物组的序列分析表征了健康和疾病中粘膜界面上存在的微生物群落，但我们对人类肠道微生物组与人粘膜免疫系统之间关系的理解仍然不完整。全基因组关联研究已经确定了许多与炎症性肠病（IBD）改变风险有关的多态性，其中许多涉及宿主防御，并可能导致营养不良，这是IBD的良好标志。不知道是否引起营养不良 通过这些变体，或者是潜在感染的结果。同样，尚不清楚IBD患者微生物组的改变是否足以促进免疫失调。实验鼠模型给出了一些见识，但是在鼠类感染模型中的疾病特征通常与人类疾病相关。此外，已经表明，鼠粘膜免疫系统的发育和成熟需要宿主特异性的肠道微生物组，需要新型的实验系统来研究人类免疫生物学。我的目标是了解人类粘膜免疫系统与人类微生物组之间的交叉调节。我已经开发了一种新型的人源性小鼠菌株，该菌株显示出适应性免疫回报，并在将HSC与突变的FOXP3一起使用时可以概括人类免疫疾病。我已经将这种菌株重新衍生为无菌条件，以允许定义的定殖策略研究人类粘膜免疫发育/功能和人类肠道微生物组的动态，从而提供了一个机会来表征在实验模型中以前未实现的正在发展的人粘膜免疫系统。我的假设是，遗传敏感性和营养不良改变了粘膜免疫发育，并导致肠道中异常的免疫反应，我将在三个目标中解决这一点：1）营养不良是否影响人类粘膜免疫系统2）是否影响遗传易感性是否能使遗传易感性造成微生物组的稳定性； 3）是否外源给微生物副产品或代谢产物潜在的人treg发育。