Histoblood group antigens, viruses & asthma excerbation

组织血型抗原、病毒

• 批准号: 7235400
• 负责人: John V Fahy
• 金额: $ 49.23万
• 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/7235400
• 关键词: Acute; Air; Allergic; Anabolism; Antigens; Apical; Aspirate substance; Asthma; Binding; Biopsy; Blood Group Antigens; Blood typing procedure; CD4 Positive T Lymphocytes; Carbohydrates; Case-Control Studies; Cell surface; Cells; Cilia; Coupled; Cultured Cells; DNA Microarray Chip; DNA Microarray format; Data; Development; Enzymes; Epithelial; Epithelial Cells; Erythrocytes; Escalator; Exhibits; Frequencies; Fucosidase; Fucosyltransferase; Genes; Glycocalyx; Glycolipids; Glycoproteins; Glycoside Hydrolases; Host Defense; Hydrolysis; Immunohistochemistry; Individual; Infection; Inflammation; Inflammatory; Interleukin-13; Interleukin-9; Irrigation; Ligands; Link; Liquid substance; Lysosomes; Mammalian Cell; Masks; Membrane Glycoproteins; Modification; Mucins; Mucous body substance; Oligosaccharides; Outpatients; Patients; Phenotype; Play; Polysaccharides; Predisposition; Production; Recording of previous events; Relative (related person); Reporting; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Rhinovirus; Risk Factors; Role; Sampling; Sputum; Stable Disease; Sterility; Structure; Surface; System; Testing; Thinking; Tight Junctions; Time; Tissue Banks; Trachea; Transferase Gene; Tunicamycin; Viral; Viral Antigens; Viral Load result; Virus; Virus Diseases; asthmatic airway; bacterial H antigen; base; blood group; carbohydrate binding protein; carbohydrate receptor; cytokine; experience; glycosylation; glycosyltransferase; human study; microorganism; novel; pathogen; programs; research study; scaffold; sugar

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）：目的是探索组织血型抗原在病毒诱导的哮喘恶化中的作用。这些抗原（ABH 和 Lewis）分别修饰粘蛋白和上皮糖蛋白上的 O 连接聚糖和 N 连接聚糖。聚糖合成涉及糖基转移酶，包括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。 “分泌者状态”由上皮细胞中的 FUT2 活性定义，其形成 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是分泌者，分泌者更频繁地报告感冒引起哮喘，并且稳定哮喘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两种相互竞争的稳态影响，a）合成聚糖的细胞内糖基转移酶的多样性和活性，b）在气道腔中翻转和重塑聚糖的糖苷酶的多样性和活性。我们假设分泌者阳性哮喘受试者容易受到病毒诱导的哮喘恶化的影响，并且分泌物中异常的糖苷酶活性会改变聚糖外壳并促进病毒诱导的恶化。在目标 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无恶化史的门诊哮喘患者的分泌状态。还将建立气道上皮细胞中分泌状态与FUT基因和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到分泌状态或岩藻糖苷酶活性的影响。在目标 4 中，我们将确定 Th2 细胞因子是否通过改变上皮细胞糖基转移酶或糖苷酶的表达来影响上皮细胞对鼻病毒感染的敏感性。 这些是对病毒引起的哮喘恶化机制的新研究，可能会促进新的治疗方法。