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（由申请方提供）：在肠道中，生命早期暴露于肠道微生物是粘膜免疫耐受和稳态发展的关键决定因素。致耐受性和稳态免疫途径的功能障碍是多种慢性炎症性疾病的基础，不仅包括克罗恩病和溃疡性结肠炎，还包括过敏症，甚至结肠直肠癌。与这些疾病相关的免疫功能障碍是复杂的，仍然不完全理解，进一步定义这些机制具有重要的临床意义。近年来，微生物组在人类健康和疾病中的作用已成为一个备受关注的领域。虽然人类微生物组的序列分析已经表征了健康和疾病中粘膜界面处存在的微生物群落，但我们对人类肠道微生物组与人类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）风险改变相关的多态性，其中许多多态性参与宿主防御，并可能导致生态失调，这是IBD的一个公认标志。目前尚不清楚生态失调是否是由 或者是潜在炎症的结果。同样，目前还不清楚IBD患者微生物组的改变是否足以促进免疫失调。实验鼠模型已经给出了一些见解，但炎症鼠模型中的疾病特征通常与人类疾病相关性很差。此外，已经表明，小鼠粘膜免疫系统的发育和成熟需要宿主特异性肠道微生物组，从而需要新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和人类微生物组之间的交叉调节。我已经开发出一种新的人源化小鼠品系，其显示适应性免疫应答，并且当使用具有突变的FOXP 3的HSC时可以重现人类免疫疾病。我已经将该菌株重新衍生到无菌条件下，以允许确定的定殖策略来研究人类粘膜免疫发育/功能和人类肠道微生物组的动力学，从而为表征先前在实验模型中未实现的发育中的人类粘膜免疫系统提供了机会。我的假设是，遗传易感性和生态失调都会改变粘膜免疫发育，并导致肠道中异常的免疫反应，我将在三个目标中解决这个问题：1）生态失调是否影响人类粘膜免疫系统2）遗传易感性是否扰乱微生物组稳定性3）微生物副产物或代谢物的外源性给药是否增强人类Treg发育。