ZONULIN AND DIABETES

连蛋白与糖尿病

• 批准号: 7376929
• 负责人: DEBRA R COUNTS
• 金额: $ 1.39万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7376929
• 关键词: ZONULIN; DIABETES

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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。 1 型糖尿病是由于体内一种称为“自身免疫”的过程导致胰腺产生胰岛素的细胞丧失而引起的，在这种过程中，身体会破坏自身的细胞。 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。一种理论认为，可能涉及通过肠道吸收的作为“抗原”的蛋白质或其他化学物质。体内有一种称为连蛋白的蛋白质，可以吸收肠道中的颗粒。已发现连蛋白在 1 型糖尿病动物模型中增加。 1 型糖尿病的问题是环境触发因素是什么，以及这些触发因素如何与免疫系统相互作用。环境因素和遗传因素之间的相互作用导致异常的免疫反应，从而导致疾病的发生。 假设：在人类中，蛋白质连蛋白的增加导致肠道吸收增加，这反过来又允许颗粒通过肠道屏障，从而触发自身免疫反应，导致胰岛素产生细胞被破坏，从而导致类型1 糖尿病。 具体目标/方法： 目标 1. 确定血液连蛋白水平是否与 1 型糖尿病肠道吸收增加相关 对 1 型糖尿病儿童及其一级亲属（父母和兄弟姐妹）进行研究，以评估连蛋白水平，以确定是否存在相关性与糖尿病发病年龄、糖尿病持续时间、与糖尿病发展相关的抗体的存在以及基因分型有关。还将评估个体体内连蛋白随时间的变化以及与血糖控制的关系。将通过测量体内通常不存在的糖的吸收来评估吸收。 目标2.从分子水平研究肠道吸收系统在1型糖尿病中的功能：意大利合作者对1型糖尿病患者进行了肠道活检，发现连蛋白水平升高，我们将研究这些样本的遗传水平通过电子显微镜观察关键结构元件的表达和肠壁结构。 意义：这些研究对 1 型糖尿病具有重要意义，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来防止胰岛素产生细胞的自身免疫破坏。初步动物研究表明，连蛋白的作用（以及因此肠道对颗粒的吸收）可以被阻断，并且胰岛素产生细胞/1型糖尿病的破坏进程也可以被阻断。