BIOLOGY OF IL-4 RECEPTOR ALLELIC VARIANTS

IL-4 受体等位基因变体的生物学

• 批准号: 6751210
• 负责人: Gurjit K. Khurana Hershey
• 金额: $ 25.9万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6751210
• 关键词: alleles; asthma; atopy; clinical research; cytokine receptors; genetic polymorphism; genetic susceptibility; genotype; human population study; human subject; interleukin 4; tissue /cell culture; transfection

This is the first revision of a proposal by a New Investigator to look at potential genetic abnormalities that may predispose individuals to asthma. The cytokine IL-4 has been shown to be important in the development of many asthmatic lesions. IL-4 binds to the IL-4 receptor alpha (IL-4Ra). This group previously has described a novel allele of IL-4Ra in which Arg replaces glutamine at position 576. This allele, named the R576 IL-4Ra allele, correlates with a ninefold increase in atopy risk, and is also associated with increased IL-4 responsiveness. There are now at least five additional polymorphic variants of IL-4Ra, and the purpose of this application is to determine the effects of each of the IL-4Ra variants, alone and in combination, on IL-4 responsiveness and the asthmatic phenotype in humans. The applicants propose to introduce missense mutations for each of the IL-4Ra alleles into the human IL-4Ra cDNA, and to transfect them into murine B cells. They then will analyze the transfectants with respect to IL-4 sensitivity and temporal responsiveness to IL-4, specifically related to activation of STAT6 and expression of CD23. They then wish to genotype a cohort of well-characterized asthmatic patients and to identify the specific IL-4Ra alleles as markers of asthma risk or severity. Finally, they wish to look at STAT6 activation and CD23 expression in A202.1 murine B cells, as used in the first aim, after cotransfection with combinations of the different allelic variants.

这是新调查员对提案的首次修订 看潜在的遗传异常，可能使个体易于 哮喘。细胞因子IL-4已被证明在开发中很重要 许多哮喘病变。 IL-4与IL-4受体α（IL-4RA）结合。这 小组以前已经描述了IL-4RA的新等位基因，其中Arg替代了 位置576的谷氨酰胺。该等位基因命名为R576 IL-4RA等位基因， 与特应性风险增加九倍有关，也与 IL-4响应性提高。现在至少还有五个 IL-4RA的多态性变体，此应用的目的是 确定单独和组合的每个IL-4RA变体的影响 关于人类的IL-4反应性和哮喘表型。申请人 建议将每个IL-4RA等位基因的错义突变引入 人IL-4RA cDNA，并将其转染到鼠B细胞中。然后他们会 分析针对IL-4灵敏度和时间的转染物 对IL-4的响应性，与STAT6的激活特别相关 CD23的表达。然后，他们希望基因类型 哮喘患者并确定特定的IL-4RA等位基因作为标记 哮喘风险或严重程度。最后，他们希望查看STAT6激活和 在第一个目的中使用的A202.1鼠B细胞中的CD23表达，之后 与不同等位基因变体的组合共转染。