Zonulin and cytokines as markers of autoimmunity in Type 1 diabetes

描述(由申请人提供)：长期目标是调查面筋摄取、依赖氮胞苷的肠道通透性持续增加和1型糖尿病发病之间的可能联系，以便制定治疗该疾病的策略，并最终制定预防方法。一些研究表明，由zonrin介导的肠道紧密连接改变导致的肠道通透性增加可能参与了包括1型糖尿病在内的自身免疫性疾病的发病机制。面筋被认为是1型糖尿病发病机制中可能的环境诱因之一。我们开发了一种新的机制方法，基于对带蛋白系统改变的患者的识别，来评估面筋在胰岛β细胞自身免疫破坏中的作用。这项建议的主要具体目标是：1)评估带蛋白和人类白细胞抗原作为1型糖尿病发展的标志；2)评估带蛋白升高和无麸质饮食(GFD)后新发的1型糖尿病儿童外周血单核细胞(PBMC)细胞因子的表达。这种饮食干预措施正在评估其对新诊断为1型糖尿病儿童的胰岛β细胞团的保存效果。如果这一策略被证明是成功的，可以防止胰岛β细胞的进一步丧失。第一个目标是通过在有T1D发展风险的儿童中连续采集样本中的zonlin进行检测。对于第二个目标，将被随机分为对照组(正常饮食)和干预(无麸质饮食)组中15名新发糖尿病儿童，并在基线时连续评估PBMC细胞因子、胰岛β细胞储备(通过C-肽刺激试验)和氮蛋白，然后每隔3个月评估一次，为期一年。与公共卫生的相关性：这项研究的目标是评估zonrin作为T1D风险的标记的作用，以及zonrin和细胞因子作为t1d自身免疫进展的标记的作用。如果成功，这些标记可以用于检测高危患者以制定有针对性的预防策略，并评估对新发糖尿病儿童的干预的成功。

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.