ST6Gal-1 Sialyltransferase in Allergic Airway Inflammation

描述(申请人提供)：哮喘是一种慢性炎症疾病，以呼吸道阻塞的周期性急性加重为特征，早期亚临床嗜酸性肺炎先于儿童哮喘的发展。为什么某些人会患上哮喘以及导致急性加重的因素仍然知之甚少。ST6Gal-1唾液酸基转移酶构建唾液酸基12，6到Gal21，4GlcNAc糖链结构。我们的初步数据表明，ST6Gal-1在调节实验性过敏性呼吸道炎症中发挥了以前未被认识到的作用。ST6Gal-1缺乏的突变小鼠夸大了急性过敏性呼吸道炎症。重组ST6Gal-1体内表达可减轻肺嗜酸粒细胞增多，提示ST6Gal-1具有治疗潜力。在诱导实验性过敏性呼吸道炎症后，ST6Gal-1表达正常的野生型小鼠循环中ST6Gal-1水平显著降低。因此，自然循环ST6Gal-1水平和血清唾液酸化产物可能有可能识别过敏性呼吸道疾病的风险人群，并作为疾病严重程度的标志。这是一项探索性的建议，旨在检验ST6Gal-1可以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作为治疗靶点的作用。具体地说，我们建议1)确定ST6Gal-1缺乏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可缓解肺部炎症和病理的程度；以及3)评估特应性哮喘患者在发作期和无症状期的循环ST6Gal-1水平与正常志愿者的关系。这项拟议研究的目标是为未来的努力提供基础数据，这些努力将侧重于开发ST6Gal-1作为过敏性呼吸道疾病的潜在早期预测和预后标记，并作为药物开发的治疗靶点。 公共卫生相关性：项目简介哮喘是一种慢性炎症疾病，以反复发作的急性呼吸道阻塞为特征。我们的初步研究揭示了ST6Gal-1唾液酸基转移酶在调节哮喘相关的急性肺炎症严重程度中的先前未知的作用。这是一项探索性建议，旨在确定ST6Gal-1对哮喘相关病理的影响程度，并评估ST6Gal-1作为特应性哮喘预后标志物和药物开发靶点的潜力。

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.