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，克罗恩氏炎性肠病的病因仍然未知，可能归因于遗传易感性、感染因子、免疫功能障碍和各种环境因子。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。增强的粘膜渗透性也是疾病复发的预测因素。因此，肠道屏障功能的原发性障碍构成了发病机制中的潜在疾病因素。我们已经确定了一种新的稳态调节肠通透性，积极生产和分泌的肠神经胶质细胞。我们认为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作用调节肠屏障功能。转亚硝基化是涉及类似于蛋白质磷酸化和乙酰化的翻译后修饰的信号传导机制。我们推测，S-亚硝基谷胱甘肽稳态异常构成克罗恩病导致肠屏障功能障碍的疾病机制。这一观点得到了我们初步研究结果的支持，S-亚硝基谷胱甘肽在克罗恩病患者的活检组织中恢复了肠屏障功能，但在对照组中没有炎症性肠病。鉴定s-亚硝基谷胱甘肽作为胶质细胞衍生的，小的，可溶性分子，保护上皮屏障的完整性代表了一个显着的进步，在理解细胞的相互作用，肠道屏障功能的基础。这些发现可能有助于开发与炎症屏障功能障碍相关的病理学（如克罗恩病）的新疗法。公共卫生相关性：跨上皮和内皮的屏障功能对于稳态组织调节至关重要。我们确定s-亚硝基谷胱甘肽作为一种新型的肠道屏障功能调节剂。我们推测S-亚硝基谷胱甘肽的异常稳态构成克罗恩病的一种新的发病机制。我们计划研究这一发现是否为炎症性渗透性疾病的治疗提供了一种新的方法。