Molecular Mechanisms Leading to Human Asthma

导致人类哮喘的分子机制

• 批准号: 6346729
• 负责人: JEAN-PIERRE M KINET
• 金额: $ 195.1万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6346729
• 关键词: asthma; immunogenetics; molecular genetics

DESCRIPTION (Applicant?s Abstract) Asthma is a chronic inflammatory syndrome whose common pathobiological expression is inflammation. The causes for asthma are unknown, and it is generally accepted that asthma results from an interaction between environmental and genetic factors. However, very little is known of genes that contribute to asthma. It is the goal of this SCOR to use a genetic approach to identify genes that influence mechanisms leading to the development of asthma. In addition, we will study basic mechanisms that may contribute to the asthmatic phenotype. The proposed SCOR in asthma consists of four scientific projects, with one of the projects serving as the clinical component. Each of these projects will dissect pathways with established relevance to human asthma and will functionally evaluate genetic polymorphisms that have already been identified that may impact these pathways. Project 1: Fine mapping, and testing of candidate genes. The goal of this project is to fine map Asthma candidate genes on 12Q and to provide a population-based resource for projects 2-4 to test candidate genes in molecular pathways. Project 2: Molecular regulation of cytokine (IL-4 and INFgamma) gene expression. The cytokines IL-4 and INFgamma both have critical roles in the development of asthma. Importantly, a polymorphism in the intronic region of the INFgamma gene has been linked to a genetic predisposition for asthma. The goal of this project is to explore the different roles of NFAT proteins in regulating IL-4 gene transcription and to investigate the regulation of INFgamma gene expression, determining if the known polymorphism impacts INFgamma gene transcription. Proiect 3: Cytokine (IL-4 and IL-13) responses in human airway smooth muscle cells. The cytokines IL-4 and IL-13 have been implicated as important in the development of allergic asthma. The goal of this project is to specifically address the role of these cytokines on cultured human airway smooth muscle cells. Importantly, the relevance of known polymorphisms in the IL-4 and IL-13 receptors will be addressed. Project 4: Regulation of IgE receptor expression and function. The IgE/FceRI network plays a central role in allergic inflammation. IgE regulates FceRI expressior that in turn regulates FceRI mediated effector functions. The goal of this project is to dissect the process of IgE-mediated FceRI expression at the molecular level with a special emphasis placed on understanding the role of the receptor beta gene in this process. Specifically, the impact of known polymorphisms in the beta gene that are associated with asthma and atopy will be assessed. Taken together, the basic science projects combined with the clinical component in this SCOR will result in an increased understanding of mechanisms that contribute to the onset of asthmatic disease. It is hoped that these combined investigations in this SCOR will provide a platform for further gene discoveries and functional evaluations relevant to asthma.

描述（申请人？s摘要） 哮喘是一种慢性炎症综合征，其常见的病理生物学 表达是炎症。哮喘的病因尚不清楚， 人们普遍认为哮喘是由 环境和遗传因素。然而，很少有人知道基因， 有助于哮喘。该SCOR的目标是使用遗传方法， 确定影响哮喘发生机制的基因。 此外，我们还将研究可能有助于 哮喘表型拟议的哮喘SCOR包括四项科学研究， 项目，其中一个项目作为临床部分。中的每 这些项目将剖析与人类相关的途径， 哮喘，并将在功能上评估基因多态性， 可能会影响这些途径。项目1：精细绘图， 测试候选基因。该项目的目标是精细绘制哮喘 12 Q上的候选基因，并为项目提供基于人群的资源 2-4来测试分子通路中的候选基因。项目2：分子 调节细胞因子（IL-4和INF γ）基因表达。细胞因子IL-4 和INF γ在哮喘的发展中都起着关键作用。 重要的是，INF γ基因内含子区的多态性使 与哮喘的遗传易感性有关这个项目的目标 探讨NFAT蛋白在调节IL-4基因中的不同作用 转录并研究INF γ基因表达的调节， 确定所述已知多态性是否影响INF γ基因转录。 项目3：人气道平滑肌中的细胞因子（IL-4和IL-13）反应 细胞细胞因子IL-4和IL-13已经被认为在免疫应答中是重要的。 过敏性哮喘的发展该项目的目标是具体 阐明这些细胞因子对培养的人气道平滑肌的作用 细胞重要的是，IL-4和IL-13中已知多态性的相关性， 受体将被处理。项目4：IgE受体表达的调节 和功能IgE/FceRI网络在过敏性疾病中起着核心作用。 炎症IgE调节FceRI表达，或其反过来调节FceRI 介导的效应子功能。这个项目的目标是剖析 IgE介导的FceRI在分子水平上的表达过程， 重点放在了解受体β基因在这一过程中的作用， 过程具体来说，β基因中已知多态性的影响， 与哮喘和特应性相关的疾病。综合起来， 基础科学项目与临床部分相结合，在这个SCOR将 提高对有助于实现可持续发展的机制的认识， 哮喘病的发作。希望这些联合调查在 该SCOR将为进一步的基因发现和功能研究提供平台。 与哮喘相关的评估。