Genetic, Biologic, & Immunologic Determinants of Asthma

遗传、生物、

• 批准号: 6542677
• 负责人: Mario Castro
• 金额: $ 38.25万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6542677
• 关键词: T lymphocyte; acute bronchitis; asthma; atopy; cell population study; chemokine; cytokine receptors; disease /disorder etiology; disease /disorder proneness /risk; family genetics; flow cytometry; gene environment interaction; genetic polymorphism; genetic susceptibility; genotype; human subject; immunity; infant human (0-1 year); inflammation; interleukin 13; interleukin 4; longitudinal human study; patient oriented research; respiratory epithelium; respiratory syncytial virus; single strand conformation polymorphism

DESCRIPTION (provided by applicant): The overall goal of this application is to determine how specific genetic, biologic, and immunologic characteristics interact to predispose individuals to develop asthma. In that context, over the last three years, we have developed a carefully selected cohort of 206 infants with respiratory syncytial virus (RSV) bronchiolitis (the RBEL (RSV Bronchiolitis in Early Life) cohort) who are at substantial risk of developing asthma. Surprisingly, physicians have already diagnosed asthma in 40 percent of the children in the RBEL cohort. The children have had at least one year of follow-up. This project builds upon our previous work establishing the largest prospective U.S. study children with RSV bronchiolitis severe enough to require hospitalization and proposes that this study should be continued for an additional five years in order to more definitively establish the diagnosis of asthma in this cohort. The interaction of RSV with the host epithelial-immune system and underlying genetic background is unclear. Accordingly, Aim I proposes to evaluate the association between genotypes associated with atopy, the IL-4 receptor a and IL- 13 single nucleotide polymorphisms, and the development of an asthmatic phenotype in the RBEL cohort of children. Given the appropriate risk factors, RSV elicits an immune response characterized by inflammatory cell influx, especially T cells, into the airway. Accordingly, Aim II proposes to evaluate the effect of airway epithelial inflammation, demonstrated by persistent RANTES (Regulated upon Activation, Normal T-cell Expressed) expression in airway epithelial cells, on the development of an asthmatic phenotype in the RBEL cohort of children. This possibility is supported by evidence of increased RANTES expression (by mRNA stabilization) in human tracheal epithelial cells infected with RSV in vitro and in upper airway epithelial cells from RBEL infants with RSV bronchiolitis. The T cell immune response following viral infection appears to be primarily Th1-type; however, in the setting of RSV infection, there actually may be a skewing of the immune response to a Th2 phenotype early in life. Accordingly, Aim III proposes to evaluate prospectively the T cell profile, Th1 vs. Th2 phenotype, as defined by cytokine expression and other phenotypic markers, in the RBEL cohort of children who are at risk of developing an asthmatic phenotype. Therefore, this application will lead to a better understanding of the interaction of genetic, biologic, and immunologic factors following serious RSV infection which lead to the development of asthma in early life. Furthermore, we propose to develop an asthma predictive index for children with serious RSV infection based upon the findings of the studies outlined in this application. Such an index would be extremely valuable to clinicians taking care of children following a severe RSV infection to provide prognostic information and to identify children at highest risk for the development of asthma who may benefit from an early intervention or treatment.

描述（由申请人提供）：本申请的总体目标是确定特定的遗传，生物学和免疫学特征如何与倾向的个体相互作用以发展哮喘。在这种情况下，在过去的三年中，我们开发了一个精心挑选的206名患有呼吸道合胞病毒（RSV）支气管炎的婴儿（早期生命中的RSV支气管炎），他们具有严重的哮喘风险。令人惊讶的是，RBEL队列中40％的儿童中已经诊断出医生已诊断出哮喘。孩子们至少进行了一年的随访。该项目基于我们以前的工作，建立了最大的前瞻性研究儿童患有RSV细支气管炎的儿童，足以需要住院治疗，并提出应该再继续进行五年的研究，以便更明确地确定该队列中哮喘的诊断。 RSV与宿主上皮免疫系统和潜在遗传背景的相互作用尚不清楚。因此，目的我提出的目的是评估与Atopy相关的基因型，IL-4受体A和IL-13单核苷酸多态性，以及在儿童RBEL队列中哮喘表型的发展。鉴于适当的危险因素，RSV引起的免疫反应，其特征在于炎症细胞流入，尤其是T细胞进入气道。因此，AIM II提出了评估气道上皮炎症的影响，这是由持续的rantes（调节激活，正常的T表达）在气道上皮细胞中的表达对儿童Rbel cohort的哮喘表型的发展。这种可能性得到了升高的rantes表达（通过mRNA稳定）的证据支持的人类气管上皮细胞在体外感染了RSV，在患有RSV细胞毒理炎的RBEL婴儿的上皮上皮细胞中感染了RSV。病毒感染后的T细胞免疫反应似乎主要是Th1型。但是，在RSV感染的情况下，实际上可能会偏向于生命早期对TH2表型的免疫反应。因此，AIM III提出了前瞻性评估T细胞谱Th1与Th2表型，如细胞因子表达和其他表型标记所定义的，在有可能发展哮喘表型的儿童的RBEL队列中。因此，在严重的RSV感染后，这种应用将使人们更好地了解遗传，生物和免疫因素的相互作用，从而导致早期哮喘的发展。此外，我们建议根据本应用中概述的研究结果为患有严重RSV感染的儿童开发哮喘预测指数。这种指数对于在严重的RSV感染后照顾儿童以提供预后信息，并确定可能从早期干预或治疗中受益的哮喘发育风险最高的儿童，这将非常有价值。