ZAAT1D-STUDY OF ZONULIN AND ANTI-ZONULIN ANTIBODIES IN PATIENTS WITH TYPE 1 DIA

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 1型糖尿病是由胰腺的胰岛素产生细胞的损失引起的，通过体内称为“自身免疫”的过程，其中身体破坏自己的细胞。 在1型糖尿病中，这些胰岛素产生细胞的自身免疫性破坏的原因尚不清楚。 一种理论是，蛋白质或其他化学物质作为“抗原”通过肠道吸收可能参与其中。 体内的一种蛋白质，称为zonulin，能够吸收肠道中的颗粒。 已经发现在1型糖尿病的Ampere模型中，Zonulin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，这是导致疾病发作的原因。 假设：在人类中，蛋白质zonulin的增加导致肠吸收的增加，这反过来允许颗粒通过肠屏障，其充当自身免疫反应的触发器，导致胰岛素产生细胞的破坏，并因此导致1型糖尿病。 具体目标/方法：目标1。为了确定血液zonulin水平是否与1型糖尿病肠道吸收增加相关，将研究1型糖尿病儿童及其一级亲属（父母和兄弟姐妹），以评估zonulin水平，以确定是否与糖尿病发病年龄，糖尿病持续时间，糖尿病发展相关抗体的存在以及基因分型相关。 还将评估个体内zonulin随时间的变化以及与血糖控制的关系。 吸收将通过测量通常在体内不存在的糖的吸收来评估。 目标2.为了在分子水平上研究1型糖尿病肠道吸收系统的功能：意大利合作者对1型糖尿病患者进行了肠道活检，并提高了zonulin水平，我们将通过电子显微镜研究这些样品的关键结构元件的遗传表达水平和肠壁结构。 意义：这些研究对1型糖尿病有重要意义，可以更深入地了解1型糖尿病的病因。 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性破坏。 初步的动物研究表明，zonulin的作用（以及因此颗粒的肠道吸收）可以被阻断，并且胰岛素产生细胞/1型糖尿病的破坏进展也被阻断。

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.