Uncovering pathogenic anti-bacterial defense mechanisms to identify novel targets for prevention of T1D

摘要 虽然现代研究表明1型糖尿病(T1D)与肠道有关 细菌失调和渗漏，目前尚不清楚这些因素是否会导致疾病。 建立T1D的发生和进展与细菌失调之间的因果联系是 对制定有效的预防战略至关重要。其中最重要的假设是 应用是T1D之前是胰腺细菌暴露，这促进了抗- 细菌反应、胰腺炎症、胰岛炎症和自身免疫。这一假设是 根据我们的初步数据制定的配方表明：1)增强了抗菌能力 幼年T1D的反应；2)胰岛对细菌的病理反应 T1D微生物群；3)实验性胰腺炎和胰岛炎鼠模型 细菌渗入胰腺；4)阻断抗菌反应保护 因胰岛炎症而产生的胰岛。在目标1中，我们将确定人类的T1D发育是否 在细胞和体液抗菌反应之前，建立一种关联 与十二指肠微生物群有关。我们将测试对细菌有反应的MAIT细胞 在临床疾病发展之前被激活，并确定它们是否被 代表过多的细菌。接下来我们将发现，增加的抗菌免疫球蛋白A是否 在T1D中的反应针对的是过度代表的细菌。我们将对十二指肠进行剖检 并确定它是否与这些防御机制有关。在《目标2》中我们将 确定胰腺暴露在细菌中是否会导致免疫激活、胰岛炎症、 和高血糖。我们将确定胰岛是否对 与T1D相关的特定细菌包括R.gnavus、B.Dorei和S.infantarius。最后，我们 将询问胰腺暴露后炎症和胰岛素炎的介质 代表过多的细菌种类和阻止反应的测试策略。要做到这一点 任务，我们建立了一种新型的小鼠肠道生物失调和渗漏的动物模型。 测试治疗干预措施。拟议中的实验将确定致病物质 肠道代谢失调和渗漏与T1D发现新靶点的机制 预防。这些靶点将在这一应用中进行临床前测试。这份意见书是 响应U01自身免疫性疾病预防合作研究小组 (CSGADP)RFA。感兴趣的广泛领域：最适合的途径、机制和方法 切实的预防性干预措施。具体研究主题：确定和阐明 可能为预防性干预提供靶点的细胞和免疫途径。

Abstract While contemporary research has shown Type 1 diabetes (T1D) is associated with intestinal dysbacteriosis and leakage, it is not known whether these factors cause the disease. Establishing a causative link between the onset and progression of T1D and dysbacteriosis is critical for developing effective prevention strategies. The overarching hypothesis of this application is that T1D is preceded by pancreatic bacterial exposure, which promotes an anti- bacterial response, pancreatic inflammation, insulitis, and autoimmunity. This hypothesis was formulated based on our preliminary data demonstrating: 1) heightened anti-bacterial responses in juvenile T1D; 2) pathologic responses by islets to bacteria overrepresented in the T1D microbiome; 3) pancreatic inflammation and insulitis in a mouse model of experimental leakage of bacteria into the pancreas; and 4) blockade of the anti-bacterial response protects islets from insulitis. In aim 1 we will determine whether human T1D development is preceded by a cellular and humoral anti-bacterial response and establish an association with the duodenal microbiome. We will test whether bacteria-responsive MAIT cells are activated before clinical disease develops and determine if they are differentially activated by overrepresented bacteria. Next, we will discover whether the increased anti-bacterial IgA response in T1D is directed at overrepresented bacteria. We will profile the duodenal microbiome and determine if it is associated with these defense mechanisms. In aim 2 we will ascertain whether pancreatic exposure to bacteria leads to immune activation, insulitis, and hyperglycemia. We will determine whether pancreatic islets show distinct responses to specific T1D-associated bacteria including R. gnavus, B. Dorei, and S. infantarius. Lastly, we will interrogate the mediators of inflammation and insulitis following pancreatic exposure to overrepresented bacterial species and test strategies to block the response. To accomplish this task, we have established a novel mouse animal of intestinal dysbiosis and leakage to test therapeutic interventions. The proposed experiments will identify pathogenic mechanisms that link intestinal dysbiosis and leakage to T1D uncovering new targets for prevention. These targets will undergo preclinical testing in this application. This submission is responsive to the U01 Cooperative Study Group for Autoimmune Disease Prevention (CSGADP) RFA. Broad area of interest: Pathways, mechanisms, and means best suited to practical preventive interventions. Specific research topic: Identification and elucidation of cellular and immune pathways that may provide targets for preventive interventions.