Gut permeability in the pathogenesis of Type 1 diabetes

描述(由申请人提供)： 1型糖尿病患者胰岛β细胞自身免疫性破坏的触发因素尚不清楚。一些研究表明，由于肠道紧密连接(TJ)的改变而导致的肠道通透性增加可能参与了自身免疫性疾病的发病机制，包括1型糖尿病。肠上皮是最大的粘膜表面，提供了外部环境和哺乳动物宿主之间的界面。因此，当TJ系统的完整性受到损害时，对包括自身免疫性疾病在内的环境抗原的免疫反应可能会发展起来，这并不令人惊讶。在过去的10年里，我们的研究主要集中在霍乱弧菌所阐述的一种蛋白--闭锁带毒素(Zot)影响肠道TJ(3，4)功能的作用机制(S)上。我们利用Zot作为一种深入了解TJ功能调控的工具的实验导致了zonlin的发现，这是一种人类真核Zot类似物，并定义了它的一些生理和病理作用。我们将我们的发现扩展到疾病状态，包括以肠道渗漏为特征的1型糖尿病，并确定了佐菌素在其发病机制中的作用。我们应用了遗传、生物化学和生物学技术来确定激活带状蛋白系统的结构和功能要求。我们的总体假设是，一组1型糖尿病患者的肠道通透性异常增加，这会导致非自身抗原穿过肠道屏障，从而触发针对胰腺β细胞的异常自身免疫反应。我们组建了一支强大的跨学科团队，其中融合了肠道TJ病理生理学、细胞和分子生物学、儿科胃肠病学和内分泌学、糖尿病、生物统计学和人类遗传学方面的专业知识，为成功解决这一假设提供了最佳资源。这项建议的长期目标是调查依赖佐诺林的慢性肠道通透性增加与1型糖尿病发病之间的可能联系，以制定预防该疾病的策略。我们将结合使用1型糖尿病的动物模型和人类研究，以便在细胞和分子水平(应用程序的R21组件)上深入了解与1型糖尿病相关的TJ失调。在这一阶段之后，我们的GCRC将进行人体研究，旨在制定预防1型糖尿病的策略(应用程序的R33部分)，前提是我们的里程碑将实现(应用程序的里程碑部分)。

DESCRIPTION (provided by applicant): The trigger of the autoimmune destruction of pancreatic beta cells in Type 1 diabetes is unclear. Several studies suggest that an increased intestinal permeability due to alteration of intestinal tight junctions (tj) can be involved in the pathogenesis of autoimmune diseases, including Type 1 diabetes. The intestinal epithelium is the largest mucosal surface providing an interface between the external environment and the mammalian host. Therefore, it is not surprising that when the integrity of the tj system is compromised an immune response to environmental antigens, including autoimmune diseases, may develop. For the past 10 years our studies have focused on the mechanism(s) of action of a protein elaborated by Vibrio cholerae, zonula occludens toxin (Zot) that affects the competency of intestinal tj (3,4). Our experiments using Zot as a tool to gain insights into the regulation of tj function led to the discovery of zonulin, a human eukaryotic Zot analogue, and to the definition of some of its physiological and pathological roles. We extended our findings to disease states, including Type 1 diabetes, characterized by a leaky gut and established the role of zonulin in their pathogenesis. We have applied genetic, biochemical, and biological techniques to establish the structural and functional requirements to activate the zonulin system. Our overall hypothesis is that a subgroup of subjects with Type 1 diabetes experiences a zonulin-dependent abnormal increase in intestinal permeability that causes non-self antigens to cross the intestinal barrier, so triggering an aberrant autoimmune response targeting the pancreatic beta cells. We have assembled a strong interdisciplinary team in which expertise in intestinal tj pathophysiology, cellular and molecular biology, pediatric gastroenterology and endocrinology, diabetology, biostatistics, and human genetics are blend together to offer the best resources to successfully address this hypothesis. The long-term objective of this proposal is to investigate possible links between zonulin-dependent chronic increase in intestinal permeability and the onset of Type 1 diabetes in order to develop strategies for the prevention of the disease. We will use the combination of an animal model of Type 1 diabetes and human studies in order to gain insights into Type 1 diabetes-associated tj dysregulation at the cellular and molecular levels (R21 component of the application). This phase will be followed by human studies performed in our GCRC aimed at developing strategies for the prevention of Type 1 diabetes (R33 component of the application), provided that our milestones will be achieved (Milestones component of the application).