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（由申请人提供）：目的是探讨组织血型抗原在病毒诱导的哮喘加重中的作用。这些抗原（ABH和Lewis）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focusyltransferases；聚糖的降解涉及糖苷酶，包括聚焦酶。“分泌状态”是由上皮细胞中的FUT2活性定义的，它形成H抗原，并允许随后合成和分泌A、B和Lewis B抗原。在初步数据中，我们发现频繁加重的哮喘受试者比非加重者更有可能成为分泌者，分泌者更频繁地报告感冒导致哮喘，而稳定哮喘患者的痰具有异常高的聚焦酶活性。这表明气道聚糖受到两种相互竞争的同稳态影响，a)合成聚糖的细胞内糖基转移酶的多样性和活性，b)在气道管腔内翻转和改造它们的糖苷酶的多样性和活性。我们假设分泌物阳性哮喘受试者易受病毒诱导的哮喘加重，分泌物中异常的糖苷酶活性改变了聚糖外壳并促进了病毒诱导的哮喘加重。在目的1中，我们提出了一项病例对照研究，以比较住院哮喘患者和门诊哮喘患者无发作史的分泌物状态。建立气道上皮细胞分泌状态与FUT基因及组织血型抗原表达的关系。在目的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到分泌状态或聚焦酶活性的影响。在Aim 4中，我们将通过改变上皮细胞糖酵解转移酶或糖苷酶的表达来确定Th2细胞因子是否影响上皮细胞对鼻病毒感染的易感性。这些都是探究病毒诱发哮喘加重机制的新思路，可能会催生新的治疗方法。