ZONULIN AND DIABETES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。1型糖尿病是由胰腺中产生胰岛素的细胞的丧失引起的，这是由于体内一种称为“自身免疫”的过程，在这种过程中，身体会破坏自己的细胞。1型糖尿病患者胰岛素产生细胞自身免疫破坏的原因尚不清楚。一种理论认为，可能与蛋白质或其他化学物质作为“抗原”通过肠道吸收有关。体内有一种名为zonlin的蛋白质，可以吸收肠道中的微粒。在一种1型糖尿病的近亲模型中，已发现Zonlin增加。1型糖尿病的问题是什么是环境触发因素，以及这些触发因素如何与免疫系统相互作用。正是环境因素和遗传因素之间的相互作用导致了异常的免疫反应，从而导致了疾病的发生。假设：在人类中，带状蛋白的增加会导致肠道吸收的增加，进而允许颗粒通过肠道屏障，从而触发自身免疫反应，导致胰岛素产生的细胞被破坏，从而导致1型糖尿病。具体目的/方法：目的1.研究1型糖尿病儿童及其一级亲属(父母和兄弟姐妹)的血中带状蛋白水平是否与肠道吸收增加有关。将对带状蛋白水平进行研究，以确定带状蛋白水平是否与糖尿病的发病年龄、病程、是否存在与糖尿病发展相关的抗体以及基因分型有关。还将评估个体内随时间的区带蛋白变化，以及与血糖控制的关系。通过测量一种通常在体内不存在的糖的吸收来评估吸收。目的2.从分子水平上研究1型糖尿病患者肠道吸收系统的功能：意大利的合作者对1型糖尿病患者进行了肠道活组织检查，并检测了zonrin水平升高，我们将对这些样本进行研究，以了解关键结构元素的遗传表达水平和肠壁的电子显微镜结构。意义：这些研究对1型糖尿病有重要意义，有助于对1型糖尿病的病因有更多的了解。这将导致潜在的治疗方法，以防止胰岛素产生细胞的自身免疫破坏。初步的动物研究表明，带状蛋白的作用(从而阻止肠道对颗粒的吸收)可以被阻断，胰岛素产生细胞的破坏/1型糖尿病的进展也被阻止。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type 1 diabetes is caused by a loss of the insulin producing cells of the pancrease, by a process in the body called "autoimmune", in which the body destroys it's own cells. The cause of the autoimmune destruction of these insulin producing cells in Type 1 diabetes is unclear. One theory is that proteins or other chemicals acting as "antigens" absorbed through the intestine may be involved. A protein in the body, called zonulin, enables absorption of particles from the intestine. Zonulin has been found to be increased in an amimal model of Type 1 diabetes. The question in Type 1 diabetes is what are the environmental triggers, and how do these triggers interact with the immune system. It is the interaction between the environmental factors and genetics that causes the abnormal immune response that is responsible for the onset of the disease. Hypothesis: In humans, an increase in the protein zonulin leads to increase in intestinal absorption, which in turn allows passage of the particles through the intestinal barrier that act as triggers of the autoimmune response that causes destruction of the insulin productn cells and therefore causes Type 1 diabetes. Specific Aims/Methods: Aim 1. To establish whether blood zonulin levels correlates with increased intestinal absorption in Type 1 diabetes Children with Type 1 diabetes and their first degree relatives (parents and siblings) will be studied to evaluate zonulin levels to establish whether a correlation with age of onset of diabetes, duration of diabetes, presence of the antibodies related to diabetes development, and genetic typing. Changes in zonulin over time within individuals, and in relationship to blood sugar control will also be evaluated. Absorption will be evaluated by measuring absorption of a sugar that is not usually found in the body. Aim 2. To study the function of the intestinal absorption system in Type 1 diabetes at the molecular level: Italian collaborators have performed intestinal biopsies of Type 1 diabetes patients and elevated zonulin levels, and these samples will be studied by us for the level of genetic expression of key structural elements and for the structure of the intestine wall by electron microscopy. Significance: These studies have significance to Type 1 diabetes in gaining more insights into the cause of Type 1 diabetes. This will then lead to potential therapies to prevent the autoimmune destruction of insulin producing cells. Preliminary animal studies show that zonulin action (and therefore intestinal absorption of particles) can be blocked and progression to destruction of insulin producting cells/Type 1 diabetes is also blocked.