Zonulin and cytokines as markers of autoimmunity in Type 1 diabetes

连蛋白和细胞因子作为 1 型糖尿病自身免疫标志物

• 批准号: 7224584
• 负责人: DEBRA R COUNTS
• 金额: $ 14.85万
• 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: 2006-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7224584
• 关键词: autoimmunity; biomarker; cell adhesion; cell death; clinical research; cytokine; diet therapy; gastrointestinal absorption /transport; gene expression; histocompatibility typing; human therapy evaluation; human tissue; insulin dependent diabetes mellitus; longitudinal human study; medical records; pancreatic islets; patient oriented research; plant proteins; tight junctions; time resolved data

DESCRIPTION (provided by applicant): The long-term objective is to investigate possible links between gluten ingestion, zonulin-dependent sustained increase in intestinal permeability, and the onset of Type 1 diabetes in order to develop strategies for the treatment of the disease, and eventually methods for prevention as well. Several studies suggest that an increased intestinal permeability due to alteration of intestinal tight junctions, mediated by zonulin, can be involved in the pathogenesis of autoimmune diseases, including Type 1 diabetes. Gluten has been implicated as one of the possible environmental triggers involved in type 1 diabetes pathogenesis. We have developed a novel mechanistic approach, based on identification of patients with alteration of the zonulin system, to evaluate the role of gluten in the autoimmune destruction of pancreatic beta cells. The primary specific aims of this proposal are to 1) evaluate zonulin and HLA type as a marker for the development of Type 1 diabetes, and 2) evaluate peripheral blood mononuclear cell (PBMC) cytokine expression in children with elevated zonulin and new onset Type 1 diabetes following a gluten-free diet (GFD). This diet intervention is being evaluated for its effect on the preservation of pancreatic beta-cell mass in children newly diagnosed with Type 1 diabetes. This strategy, if proven successful could preventing further loss of pancreatic beta cells. The first aim is addressed by assaying zonulin in samples collected serially in children at risk for the development of T1D. For the second aim, children with elevated zonulin will be randomized, 15 children with new onset diabetes in the control (normal diet) group, 15 children in the intervention (gluten-free diet) group, and evaluated serially for PBMC cytokines, pancreatic beta-cell reserve (by C-peptide stimulation testing) and zonulin at baseline, and then at 3 month intervals for one year. Relevance to public health: The goal of this study is to evaluate the role of zonulin as a marker for T1D risk, and the role of zonulin and cytokines as a marker for autoimmune progression in T1 D. If successful, these markers could be used for detecting at risk patients for targeting prevention strategies, and also in evaluating the success of interventions for children with new onset diabetes.

描述（由申请人提供）：长期目标是研究麸质摄入、连蛋白依赖性肠道通透性持续增加和 1 型糖尿病发病之间可能存在的联系，以便制定治疗该疾病的策略，以及最终还有预防方法。多项研究表明，连蛋白介导的肠道紧密连接改变导致肠道通透性增加，可能参与包括 1 型糖尿病在内的自身免疫性疾病的发病机制。麸质被认为是 1 型糖尿病发病机制中可能的环境触发因素之一。我们开发了一种新的机制方法，基于对连蛋白系统改变的患者的识别，来评估麸质在胰腺β细胞的自身免疫破坏中的作用。该提案的主要具体目标是 1) 评估 zonulin 和 HLA 类型作为 1 型糖尿病发生的标志物，2) 评估 zonulin 升高和新发 1 型糖尿病儿童的外周血单核细胞 (PBMC) 细胞因子表达无麸质饮食（GFD）后的糖尿病。目前正在评估这种饮食干预措施对新诊断出的 1 型糖尿病儿童胰腺 β 细胞质量保存的影响。如果这一策略被证明成功，可以防止胰腺β细胞的进一步损失。第一个目标是通过对有患 T1D 风险的儿童连续收集的样本中的连蛋白进行测定来解决。对于第二个目标，连蛋白升高的儿童将被随机分组​​，对照组（正常饮食）组有 15 名新发糖尿病儿童，干预组（无麸质饮食）有 15 名儿童，并连续评估 PBMC 细胞因子、胰腺β -基线时的细胞储备（通过 C 肽刺激测试）和连蛋白，然后每隔 3 个月一次，持续一年。与公共卫生的相关性：本研究的目的是评估 zonulin 作为 T1D 风险标记物的作用，以及 zonulin 和细胞因子作为 T1D 自身免疫进展标记物的作用。如果成功，这些标记物可用于检测高危患者以制定预防策略，并评估针对新发糖尿病儿童的干预措施是否成功。