Histoblood group antigens, viruses & asthma excerbation

描述(由申请人提供)：目的是探索组织母细胞组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-和N-连接的糖链。糖的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；糖的降解涉及糖苷酶，包括岩藻糖苷酶。“分泌者状态”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患者比非加重患者更有可能是秘书，秘书更频繁地报告感冒导致哮喘，缓解期哮喘的痰具有异常高的岩藻糖苷酶活性。这表明，气道多糖受到两种相互竞争的稳态影响，a)合成多糖的细胞内糖基转移酶的多样性和活性，以及b)糖苷酶的多样性和活性，糖苷酶在气道腔中翻转和重塑它们。我们假设分泌物阳性的哮喘患者易受病毒诱导的哮喘加重的影响，分泌物中的糖苷酶活性异常改变了糖蛋白的外壳，促进了病毒诱导的哮喘加重。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加重病史的门诊哮喘患者的分泌物状态。分泌者状态与FUT基因和组织血型抗原在呼吸道上皮细胞中表达的关系也将被建立。在目标2和3中，我们将确定鼻病毒与呼吸道粘蛋白或呼吸道上皮细胞的结合是否受到分泌物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酵解转移酶或糖苷酶的表达来影响上皮细胞对鼻病毒感染的易感性。这些都是对病毒诱导的哮喘恶化机制的新的探索，并可能促使新的治疗方法。

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.