S-nitrosoglutathione regulation of intestinal barrier function in Crohn's disease

S-亚硝基谷胱甘肽对克罗恩病肠道屏障功能的调节

• 批准号: 7660261
• 负责人: Tor C. Savidge
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660261
• 关键词: Ablation; Acetylation; Animal Model; Astrocytes; Binding; Biopsy; Blood; Blood - brain barrier anatomy; Brain; Cell Line; Cerebrum; Chronic; Clinical Research; Complement; Conditioned Culture Media; Crohn' s disease; Cyclic GMP; Cysteine; Data; Development; Disease; Endothelium; Enteral; Enzymes; Epithelial; Epithelial Cells; Epithelium; Etiology; Failure; First Degree Relative; Functional disorder; Gamma-glutamyl transferase; Genetic Predisposition to Disease; Health; Homeostasis; Human; Immune System Diseases; Individual; Infectious Agent; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestinal Diseases; Intestines; Isomerism; Lateral; Measures; Mediator of activation protein; Metabolism; Neuraxis; Neuroglia; Oxidoreductase; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Peripheral; Permeability; Phosphorylation; Play; Post-Translational Protein Processing; Predictive Factor; Process; Proteins; Recurrence; Regulation; Relative (related person); Research; Rewards; Role; Signal Transduction; Specificity; Suggestion; Sulfhydryl Compounds; System; Tight Junctions; Tissues; Transgenic Animals; Transgenic Mice; base; environmental agent; high risk; novel; novel strategies; novel therapeutics; occludin; prevent; public health relevance; superoxide dismutase 1

DESCRIPTION (provided by applicant): Despite extensive research, the etiology of Crohn's inflammatory bowel disease remains unknown with possible suggestions attributed to genetic susceptibility, infectious agents, immune dysfunction, and various environmental agents. A number of clinical studies have demonstrated an increased intestinal permeability in Crohn's disease patients and in their first-degree relatives. Enhanced mucosal permeability is also a predictive factor of disease recurrence. Thus, a primary disorder of intestinal barrier function constitutes a potential disease factor in the pathogenesis. We have identified a novel homeostatic regulator of intestinal permeability that is actively produced and secreted by enteric glial cells. We propose that s-nitrosoglutathione regulates intestinal barrier function via transnitrosylation of epithelial tight-junction associated proteins. Transnitrosylation is a signaling mechanism involving post-translational modification analogous to protein phosphorylation and acetylation. We hypothesize that aberrant s-nitrosoglutathione homeostasis constitutes a disease mechanism in Crohn's disease resulting in intestinal barrier dysfunction. This view is supported by our preliminary findings that s-nitrosoglutathione restores intestinal barrier function in biopsies from Crohn's disease patients but not in control patients without inflammatory bowel disease. The identification of s-nitrosoglutathione as a glial-derived, small, soluble molecule that protects epithelial-barrier integrity represents a significant advance in the understanding of the cellular interactions that underlie intestinal barrier function. These findings may help in the development of novel therapies for pathologies, such as Crohn's disease, that are associated with inflammatory barrier dysfunction. PUBLIC HEALTH RELEVANCE: Barrier functions across epithelia and endothelia are essential for homeostatic tissue regulation. We identified s-nitrosoglutathione as a novel regulator of intestinal barrier function. We hypothesize that aberrant homeostasis of s-nitrosoglutathione constitutes a new disease mechanism in Crohn's disease. We plan to investigate whether this finding offers a novel approach to therapy for inflammatory permeability disorders.

描述（由申请人提供）：尽管进行了广泛的研究，但克罗恩氏炎症性肠病的病因仍然未知，可能的建议归因于遗传易感性、传染源、免疫功能障碍和各种环境因素。许多临床研究表明克罗恩病患者及其一级亲属的肠道通透性增加。粘膜通透性增强也是疾病复发的预测因素。因此，肠道屏障功能的原发性紊乱构成了发病机制中的潜在疾病因素。我们发现了一种新型的肠道通透性稳态调节剂，它是由肠神经胶质细胞主动产生和分泌的。我们提出，s-亚硝基谷胱甘肽通过上皮紧密连接相关蛋白的转亚硝基化来调节肠道屏障功能。转亚硝基化是一种信号传导机制，涉及类似于蛋白质磷酸化和乙酰化的翻译后修饰。我们假设异常的 s-亚硝基谷胱甘肽稳态构成了克罗恩病导致肠道屏障功能障碍的疾病机制。我们的初步研究结果支持了这一观点，即 s-亚硝基谷胱甘肽可以恢复克罗恩病患者活检中的肠道屏障功能，但不能恢复没有炎症性肠病的对照患者的肠道屏障功能。 s-亚硝基谷胱甘肽被鉴定为一种神经胶质来源的、可保护上皮屏障完整性的小可溶性分子，代表了对肠道屏障功能基础细胞相互作用的理解的重大进展。这些发现可能有助于开发新的病理疗法，例如与炎症屏障功能障碍相关的克罗恩病。公共卫生相关性：上皮和内皮细胞的屏障功能对于组织稳态调节至关重要。我们确定 s-亚硝基谷胱甘肽是肠道屏障功能的新型调节剂。我们假设 s-亚硝基谷胱甘肽的异常稳态构成了克罗恩病的一种新的疾病机制。我们计划研究这一发现是否为治疗炎症渗透性疾病提供了一种新方法。