S-Nitrosothiol Breakdown by Airway Epithelial Cells

超出所提供的空间。s -亚硝基硫醇是一氧化氮和半胱氨酸硫醇的内源性加合物。越来越多的人认识到，s -亚硝基化反应可能导致翻译后蛋白质修饰。这些修饰与不依赖于环gmp的生物活性有关，这些生物活性可能被调节为生理优势。例如，蛋白质可以通过与s -亚硝基化肽（如s -亚硝基谷胱甘肽）的转亚硝化反应进行修饰，其浓度似乎受到酶的调节。事实上，现在有几种酶被认为可以调节s -亚硝基谷胱甘肽的分解代谢，包括谷胱甘肽依赖性甲醛脱氢酶和-谷氨酰转肽酶。s -亚硝基硫醇生物化学可能参与气道内广泛的生物活性调控，包括离子通道传导、炎症细胞凋亡和气道平滑肌松弛。值得注意的是，我们最近观察到s -亚硝基谷胱甘肽增加了囊性纤维化跨膜调节蛋白（CFTR）最常见突变形式AF508的表达和成熟。囊性纤维化和哮喘患者气道中的s -亚硝基硫醇水平似乎较低，部分原因是s -亚硝基谷胱甘肽分解代谢酶活性增加。事实上，如果不是加速s -亚硝基谷胱甘肽的分解代谢，s -亚硝基谷胱甘肽替代疗法可以被设想为一种治疗囊性纤维化和哮喘的新疗法。在本项目中，我们计划1)表征s -亚硝基硫醇分解代谢在囊性纤维化和哮喘气道上皮中的调节；2)明确s -亚硝基谷胱甘肽等s -亚硝基硫醇促进AF508 CFTR成熟的机制；3)评估规避s -亚硝基谷胱甘肽分解代谢以实现气道有益生物活性的机制，包括增加CFTR成熟。我们期待这个项目将为理解囊性纤维化和哮喘的细胞生物学提供新的工具，也可能导致这两种疾病的新疗法的发展。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. S-Nitrosothiols are endogenous adducts of nitric oxide and cysteine thiols. Increasingly, it is appreciated that S-nitrosylation reactions may result in post-translational protein modifications. These modifications have been associated with cyclic GMP-independent bioactivities that may be regulated to physiological advantage. For example, proteins may be modified by transnitrosation reactions with S-nitrosylated peptides such as S-nitrosoglutathione, concentrations of which appear to be enzymatically regulated. Indeed, several enzymes are now appreciated to regulate the catabolism of S-nitrosoglutathione, including glutathione- dependent formaldehyde dehydrogenase and _,-glutamyl transpeptidase. S-nitrosothiol biochemistry may be involved in the regulation of a broad spectrum of bioactivities in the airway, including ion channel conductivity, inflammatory cell apoptosis and airway smooth muscle relaxation. Of note, we have recently observed that S-nitrosoglutathione increases the expression and maturation of the most common mutant form of cystic fibrosis transmembrane regulatory protein (CFTR), AF508. Levels of S-nitrosothiols appear to be low in the airways of patients with both cystic fibrosis and with asthma, in part because of increased activity of S-nitrosoglutathione catabolic enzymes. Indeed, were it not for accelerated S-nitrosoglutathione catabolism, S-nitrosoglutathione replacement therapy could be envisioned as a novel therapy for both cystic fibrosis and asthma. In this project, we plan to 1) characterize the regulation of S-nitrosothiol catabolism in the cystic fibrosis and asthmatic airway epithelium; 2) define the mechanism by which S-nitrosoglutathione and other S-nitrosothiols may increase the maturation of AF508 CFTR; and 3) evaluate mechanisms by which S-nitrosoglutathione catabolism might be circumvented to achieve salutary bioactivities in the airways, including increased CFTR maturation. We anticipate that this project will provide new tools for understanding the cell biology of cystic fibrosis and asthma, and that it may also lead to the development of new therapies for both diseases. PERFORMANCE SITE ========================================Section End===========================================