ST6Gal-1 Sialyltransferase in Allergic Airway Inflammation

描述（由申请人提供）：哮喘是一种慢性炎症疾病，以周期性的气道阻塞急性加重为特征，儿童早期亚临床嗜酸性粒细胞性肺部炎症先于哮喘的发展。为什么某些人会患上哮喘，以及导致急性发作严重程度的因素仍然知之甚少。ST6Gal-1唾液基转移酶构建唾液基12,6到gal21,4 glcnac聚糖结构。我们的初步数据表明，ST6Gal-1在调节实验性过敏性气道炎症中的作用以前未被认识到。ST6Gal-1缺陷突变小鼠急性过敏性气道炎症加重。重组ST6Gal-1在体内的表达可以减弱肺嗜酸性粒细胞增多症，提示ST6Gal-1具有治疗潜力。在诱导实验性过敏性气道炎症后，ST6Gal-1表达谱正常的野生型小鼠循环ST6Gal-1水平明显降低。因此，自然循环ST6Gal-1水平和血清唾液化产物可能具有识别过敏性气道疾病风险人群的潜力，并作为疾病严重程度的标志。本研究旨在验证ST6Gal-1调节过敏性呼吸道炎症的假设，并评估ST6Gal-1作为哮喘疾病严重程度的标志物和治疗靶点。具体来说，我们建议：1)确定ST6Gal-1缺失的突变小鼠肺部炎症和哮喘样病理的影响程度；2)确定体内补充ST6Gal-1对肺部炎症和病理的缓解程度；3)评估特应性哮喘加重期和无症状期患者与正常受试者循环ST6Gal-1水平的关系。拟议研究的目标是为未来的努力提供基础数据，将重点放在开发ST6Gal-1作为过敏性气道疾病的潜在早期预测因子和预后标记物以及作为药物开发的治疗靶点。

DESCRIPTION (provided by applicant): Asthma is a disease of chronic inflammation marked by periodic bouts of acute exacerbations of airway obstruction, and early sub-clinical eosinophilic pulmonary inflammation precedes the development of asthma in children. Why certain individuals develop asthma and factors contributing to the severity of acute exacerbations remain poorly understood. The ST6Gal-1 sialyltransferase constructs the sialyl 12,6 to Gal21,4GlcNAc glycan structures. Our preliminary data point to a previously unrecognized role of ST6Gal-1 in modulating experimental allergic airway inflammation. Mutant mice with ST6Gal-1 deficiencies have exaggerated acute allergic airway inflammation. Expression of recombinant ST6Gal-1 in vivo can attenuate the pulmonary eosinophilia, suggesting a therapeutic potential for ST6Gal-1. Following induction of experimental allergic airway inflammation, wild-type mice with normal ST6Gal-1 expression profiles had significantly depressed circulatory ST6Gal-1 levels. Therefore, natural circulatory ST6Gal-1 levels and serum sialylation products may have potential in identifying persons at risk for allergic airway disease and as a marker for disease severity. This is an exploratory proposal to test the hypothesis that ST6Gal-1 can regulate allergic respiratory inflammation and to evaluate ST6Gal-1 as a marker for asthma disease severity and as a therapeutic target. Specifically, we propose to 1) determine the extent that pulmonary inflammation and asthma-like pathologies are affected in mutant mice with deficiencies in ST6Gal-1; 2) determine the extent that pulmonary inflammation and pathologies can be mitigated by in vivo supplementing of ST6Gal-1; and 3) assess the relationship of circulatory ST6Gal-1 levels in patients with atopic asthma during exacerbations and asymptomatic periods, and normal volunteers. The goal of the proposed research is to generate the foundation data for future efforts that will focus on developing ST6Gal-1 as a potential early predictor and prognostic marker of allergic airway disease and as a therapeutic target for drug development. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Asthma is a disease of chronic inflammation marked by recurring acute bouts of airway obstruction. Our preliminary studies have revealed a previously unrecognized role for the ST6Gal-1 sialyltransferase in modulating the severity of the acute pulmonary inflammation underlying asthma. This is an exploratory proposal to determine the extent that asthma-related pathologies are affected by ST6Gal-1, and to evaluate the potential of ST6Gal-1 as a prognostic marker in atopic asthma and as a target for drug development.