Autoimmune Diabetes: Gut Microbial Regulation in the IL10KO Mouse Model

自身免疫性糖尿病：IL10KO 小鼠模型中的肠道微生物调节

• 批准号: 9145480
• 负责人: Alexandria Marie Bobe
• 金额: $ 4.36万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9145480
• 关键词: Adoptive Transfer; Affect; Age; American; Anatomy; Anti-Inflammatory Agents; Anti-inflammatory; Architecture; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Biological Response Modifiers; Blood Glucose; Cells; Chronic; Chronic Disease; Clinical; Colitis; Complex; Data; Development; Disease; Distal; Environmental Risk Factor; Ethnic group; Exhibits; Female; Functional disorder; Genetic; Genetic Risk; Germ-Free; Goals; Helicobacter; Immune; Immune response; Immune system; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Intestines; Investigation; Islet Cell; Knock-out; Knockout Mice; Life; Lymphatic System; Mediating; Mediator of activation protein; Metabolism; Microbe; Modeling; Molecular; Mono-S; Mucous Membrane; Mus; Nature; Onset of illness; Organ; Outcome; Pancreas; Pathogenesis; Play; Prevalence; Prophylactic treatment; Regulation; Research; Risk; Role; Site; Small Intestines; Structure; Susceptibility Gene; Testing; Therapeutic; Therapeutic immunosuppression; Time; Wild Type Mouse; Work; base; blood glucose regulation; cell type; cytokine; diabetic; disease phenotype; disorder prevention; germ free condition; gut microbiota; immune function; immunopathology; in vivo; insight; interdisciplinary approach; islet; male; microbial; microbial community; microbial host; microbiome; microbiota; microorganism interaction; mouse model; novel; potential biomarker; probiotic therapy; public health relevance; response

 DESCRIPTION (provided by applicant): Autoimmunity, the aberrant regulation of the immune system, affects an astounding 23.5 million Americans. Autoimmune disease such as Type 1 diabetes (T1D) and Inflammatory Bowel Diseases (IBD) are major causes of chronic illness and are expected to rise with increasing prevalence across all ethnic groups. Disruptions in gut microbial communities (dysbiosis) are highly associated with both T1D and IBD; however, the importance of gut microbes as regulators of disease pathophysiology has only recently been highlighted. The interleukin-10 deficient (IL10KO) mouse is a well-established model of IBD; however germ-free (GF) IL10KO mice never develop colonic inflammation. We made the novel discovery that GF IL10KO mice instead develop pancreatic infiltration that remarkably resembles clinical T1D insulitis. The IL10KO model is an exciting opportunity to investigate the role of gut microbes as regulators of immunopathology that mediate T1D and/or the complex interplay between host-microbial interactions and immunological regulation in disease. Determine whether GF IL10KO mice exhibit an increased risk for insulitis associated with Type 1 diabetes and identify the immune mediators in GF IL10KO compared to conventionally-raised counterparts ; [2] Determine the role of gut microbes and mucosal immune function in protection against insulitis in IL10 KO mice. A multidisciplinary approach using immunological, histological, and molecular strategies will identify (1) the window of time insulitis is initiated, (2) specific immune cell types involved in immunopathology, as well as potential biomarkers of disease, and (3) the impact of insulitis on islet architecture and host blood glucose homeostasis. In vivo approaches will test the IBD phenotypes, demonstrating Two central aims are proposed: [1] transferability of autoimmune-mediated pathophysiology via adoptive transfer models and whether introduction of specific microbes at an early window of life protects against insulitis. This model has the potential to open many avenues to discovery in the fields of metabolism, autoimmunity, genetics, and microbiome; and warrants further characterization to investigate mechanisms of disease. The proposed research will provide fundamental information about autoimmune initiation and progression in the pancreas and the premise for preventative probiotic therapies to decrease the incidence of T1D.

 描述（由申请人提供）：自身免疫，免疫系统的异常调节，影响了惊人的2350万美国人。自身免疫性疾病，如1型糖尿病（T1 D）和炎症性肠病（IBD）是慢性疾病的主要原因，预计将随着所有种族人群的患病率增加而增加。肠道微生物群落的破坏（生态失调）与T1 D和IBD高度相关;然而，肠道微生物作为疾病病理生理学调节因子的重要性最近才得到强调。白细胞介素-10缺陷型（IL 10 KO）小鼠是一种成熟的IBD模型;然而，无菌（GF）IL 10 KO小鼠从未发生结肠炎症。我们有了新的发现，GF IL 10 KO小鼠反而发生了与临床T1 D胰岛炎非常相似的胰腺浸润。IL 10 KO模型是一个令人兴奋的机会，可以研究肠道微生物作为免疫病理学调节因子的作用，这些调节因子介导T1 D和/或宿主-微生物相互作用与疾病中的免疫调节之间的复杂相互作用。确定GF IL 10 KO小鼠是否表现出与1型糖尿病相关的胰岛炎风险增加，并确定GF IL 10 KO中的免疫介质与常规饲养的对应物相比; [2]确定肠道微生物和粘膜免疫功能在IL 10 KO小鼠中保护免受胰岛炎的作用。采用免疫学、组织学和分子策略的多学科方法将确定（1）胰岛炎启动的时间窗，（2）免疫病理学中涉及的特定免疫细胞类型，以及疾病的潜在生物标志物，和（3）胰岛炎对胰岛结构和宿主血糖稳态的影响。体内方法将测试IBD表型，证明提出了两个中心目标：[1]通过过继转移模型的自身免疫介导的病理生理学的可转移性，以及在生命早期窗口引入特定微生物是否可以预防胰岛炎。该模型有可能为代谢、自身免疫、遗传学和微生物组领域的发现开辟许多途径;并保证进一步表征以研究疾病机制。拟议的研究将提供有关胰腺自身免疫启动和进展的基本信息，以及预防性益生菌治疗以降低T1 D发病率的前提。