ST6Gal-1 Sialyltransferase in Allergic Airway Inflammation

ST6Gal-1 唾液酸转移酶在过敏性气道炎症中的作用

• 批准号: 7588169
• 负责人: Joseph TY Lau
• 金额: $ 29.75万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588169
• 关键词: Acute; Affect; Allergens; Allergic; Animals; Asthma; Attenuated; Automobile Driving; Cells; Childhood Asthma; Chronic; Chronic Disease; Clinical; Data; Developed Countries; Developing Countries; Development; Diagnostic; Disease; Exhibits; Extrinsic asthma; Foundations; Funding; Future; Goals; Grant; Health; Hepatic; Homeostasis; Human; Human Characteristics; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Interleukin-5; Knockout Mice; Lung; Modeling; Molecular Profiling; Monitor; Mus; Mutant Strains Mice; Ovalbumin; Pathogenesis; Pathology; Pathway interactions; Patients; Persons; Pneumonia; Polysaccharides; Prognostic Marker; Pulmonary Eosinophilia; Recombinants; Recurrence; Research; Risk; Role; ST6Gal I; Serum; Severities; Severity of illness; Sialyltransferases; Small inducible cytokine A24; Structure; Testing; Therapeutic; Transgenic Mice; United States National Institutes of Health; Wild Type Mouse; airway inflammation; airway obstruction; allergic airway disease; allergic airway inflammation; asthmatic patient; attenuation; base; cytokine; depressed; drug development; eosinophil; experience; granulocyte; in vivo; insight; novel; public health relevance; respiratory; response; sialylation; therapeutic target; volunteer

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.

描述（由申请人提供）：哮喘是一种慢性炎症疾病，其特征是气道阻塞的急性加重的周期性发作，并且在儿童哮喘发展之前出现早期亚临床嗜酸性肺部炎症。为什么某些人发展为哮喘和导致急性加重的严重性的因素仍然知之甚少。ST 6 Gal-1唾液酸转移酶构建唾液酸12，6至Gal 21，4GlcNAc聚糖结构。我们的初步数据表明，以前未被认识到的作用，ST 6 Gal-1在调节实验性过敏性气道炎症。ST 6 Gal-1缺陷的突变小鼠具有夸大的急性过敏性气道炎症。重组ST 6 Gal-1在体内的表达可以减弱肺嗜酸性粒细胞增多症，表明ST 6 Gal-1的治疗潜力。在诱导实验性过敏性气道炎症后，具有正常ST 6 Gal-1表达谱的野生型小鼠的循环ST 6 Gal-1水平显著降低。因此，自然循环ST 6 Gal-1水平和血清唾液酸化产物可能具有识别过敏性气道疾病风险的潜力，并作为疾病严重程度的标志物。这是一个探索性的建议，以测试的假设，ST 6 Gal-1可以调节过敏性呼吸道炎症和评估ST 6 Gal-1作为哮喘疾病的严重程度的标志物和作为一个治疗目标。具体地，我们提出1）确定在具有ST 6 Gal-1缺陷的突变小鼠中肺部炎症和哮喘样病理受影响的程度; 2）确定通过体内补充ST 6 Gal-1可以减轻肺部炎症和病理的程度;和3）评估在急性发作期和无症状期的特应性哮喘患者和正常志愿者中循环ST 6 Gal-1水平的关系。拟议研究的目标是为未来的努力产生基础数据，这些努力将集中于开发ST 6 Gal-1作为过敏性气道疾病的潜在早期预测因子和预后标志物，并作为药物开发的治疗靶点。 哮喘是一种慢性炎症性疾病，以反复发作的急性气道阻塞为特征。我们的初步研究揭示了ST 6 Gal-1唾液酸转移酶在调节哮喘急性肺部炎症严重程度中的作用。这是一个探索性的建议，以确定哮喘相关的病理受ST 6 Gal-1的影响程度，并评估ST 6 Gal-1作为特应性哮喘的预后标志物和作为药物开发的目标的潜力。