NONINFLAMMATORY GLUTEN PEPTIDE ANALOGUES AS BIOMARKERS FOR CELIAC SPRUE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 需要新的工具来管理乳糜泻，这是一种终生的小肠免疫性疾病。正在进行的药物试验也促使人们寻找面筋引起的肠道改变的非侵入性生物标志物。我们已经合成并表征了非炎症性谷蛋白多肽类似物，其中关键的谷氨酰胺残基被天冬氨酸或组氨酸取代。像促炎症的生物标志物一样，这些生物标志物对胃肠道蛋白酶具有抵抗力，对谷氨酸酶敏感，并可透过肠道细胞屏障。然而，与面筋多肽不同的是，它们不能被转谷氨酰胺酶、人类白细胞抗原DQ2或疾病特异性T细胞识别。体外和动物研究表明，这些生物标志物可以检测到肠道通透性的变化，以及谷氨酸酶催化的胃面筋解毒作用。因此，有必要进行对照临床研究，以评估这些多肽在临床试验和实践中作为检测肠道通透性异常和谷氨酸酶疗效的探针的作用。

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. New tools are needed for managing celiac sprue, a lifelong immune disease of the small intestine. Ongoing drug trials are also prompting a search for non-invasive biomarkers of gluten-induced intestinal change. We have synthesized and characterized non-inflammatory gluten peptide analogues in which key Gln residues are replaced by Asn or His. Like their pro-inflammatory counterparts, these biomarkers are resistant to gastrointestinal proteases, susceptible to glutenases, and permeable across enterocyte barriers. Unlike gluten peptides, however, they are not appreciably recognized by transglutaminase, HLA-DQ2 or disease-specific T cells. In vitro and animal studies show that the biomarkers can detect intestinal permeability changes as well as glutenase-catalyzed gastric detoxification of gluten. Accordingly, controlled clinical studies are warranted to evaluate the use of these peptides as probes for abnormal intestinal permeability in celiac patients and for glutenase efficacy in clinical trials and practice.