Histoblood group antigens, viruses & asthma excerbation

组织血型抗原、病毒

• 批准号: 6913850
• 负责人: John V Fahy
• 金额: $ 53.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6913850
• 关键词: asthma; blood group antigens; clinical research; common cold; disease /disorder proneness /risk; enzyme activity; fucose; genetic susceptibility; glycosidases; hexosyltransferase; human subject; human tissue; immunocytochemistry; immunogenetics; microarray technology; mucins; patient oriented research; respiratory epithelium; respiratory infections; rhinovirus; virus infection mechanism

DESCRIPTION (provided by applicant): The objective is to explore the role of histoblood group antigens in virus-induced asthma exacerbations. These antigens (ABH and Lewis) decorate O- and N-linked glycans on mucin and epithelial glycoproteins, respectively. Glycan synthesis involves glycosyltransferases, including fucosyltransferases encoded by FUT genes; glycan degradation involves glycosidases, including fucosidase. "Secretor status" is defined by FUT2 activity in epithelial cells, which forms the H antigen and allows subsequent synthesis and secretion of A, B, and Lewis B antigens. In preliminary data, we found that asthmatic subjects with frequent exacerbations are more likely than non-exacerbators to be secretors, that secretors more frequently report that a cold causes asthma, and that sputum in stable asthma has abnormally high fucosidase activity. This suggests that airway glycans are subjected to 2 competing homoeostatic influences, a) the diversity and activity of glycosyltransferases within cells that synthesize glycans, and b) the diversity and activity of glycosidases that turn over and remodel them in the airway lumen. We hypothesize that secretor positive asthmatic subjects are susceptible to virus-induced asthma exacerbation and that abnormal glycosidase activity in secretions modifies the glycan coat and promotes virus-induced exacerbation. In Aim 1, we propose a case control study to compare secretor status in hospitalized asthmatics and outpatient asthmatics without a history of exacerbation. The relationships between secretor status and FUT gene and histo-blood group antigen expression in airway epithelial cells will also be established. In Aims 2 and 3, we will determine if binding of rhinovirus to airway mucins or to airway epithelial cells is influenced by secretor status or by fucosidase activity. In Aim 4 we will determine if Th2 cytokines influence epithelial cell susceptibility to rhinovirus infection by changing epithelial cell expression of glycolytransferases or glycosidases. These are novel lines of inquiry into the mechanisms of virus-induced asthma exacerbation and may prompt novel treatments.

描述（由申请方提供）：目的是探索组织抗原组抗原在病毒诱导的哮喘急性发作中的作用。这些抗原（ABH和刘易斯）分别修饰粘蛋白和上皮糖蛋白上的O-和N-连接聚糖。聚糖合成涉及糖基转移酶，包括由FUT基因编码的岩藻糖基转移酶;聚糖降解涉及糖苷酶，包括岩藻糖苷酶。“分泌状态”由上皮细胞中的FUT 2活性定义，其形成H抗原并允许随后合成和分泌A、B和刘易斯B抗原。在初步数据中，我们发现，哮喘患者频繁加重比非急性加重更可能是分泌型，分泌型更频繁地报告感冒引起哮喘，稳定型哮喘患者的痰液具有异常高的岩藻糖苷酶活性。这表明气道聚糖受到2种竞争性同源平衡影响，a）合成聚糖的细胞内糖基转移酶的多样性和活性，以及B）在气道腔中翻转和重塑聚糖的糖基化酶的多样性和活性。我们假设分泌物阳性的哮喘受试者对病毒诱导的哮喘急性发作易感，并且分泌物中的糖苷酶活性异常改变聚糖涂层并促进病毒诱导的急性发作。在目的1中，我们提出了一个病例对照研究，以比较分泌状态的住院哮喘患者和门诊哮喘无加重史。本研究也将建立呼吸道上皮细胞分泌状态与FUT基因及组织血型抗原表达之间的关系。在目标2和3中，我们将确定鼻病毒与气道粘蛋白或气道上皮细胞的结合是否受分泌状态或岩藻糖苷酶活性的影响。在目的4中，我们将确定Th 2细胞因子是否通过改变上皮细胞糖基转移酶或糖基化酶的表达来影响上皮细胞对鼻病毒感染的易感性。 这些是对病毒诱导的哮喘急性发作机制的新的调查路线，并可能促进新的治疗方法。