Molecular Mechanisms Leading to Human Asthma

描述(申请人--S摘要) 哮喘是一种慢性炎症性综合征，其共同的病理生物学特征 表现为炎症。哮喘的原因尚不清楚， 人们普遍认为，哮喘是由以下因素相互作用造成的 环境和遗传因素。然而，人们对这些基因知之甚少。 会导致哮喘。这一SCOR的目标是使用遗传方法来 确定影响导致哮喘发生的机制的基因。 此外，我们将研究可能有助于 哮喘表型。建议的哮喘SCOR由四项科学指标组成 项目，其中一个项目作为临床组成部分。每一个 这些项目将剖析已建立的与人类相关的途径 并将对已经存在的基因多态性进行功能性评估 已发现可能影响这些途径的基因。项目1：精细测绘，以及 对候选基因的测试。这个项目的目标是精确绘制哮喘地图。 12Q上的候选基因，并为项目提供基于群体的资源 2-4测试分子途径中的候选基因。项目2：分子 细胞因子(IL-4和INF-γ)基因表达的调节。细胞因子IL-4 和INFGamma在哮喘的发生发展中都起着关键作用。 重要的是，INFGamma基因内含子区域的多态具有 与哮喘的遗传易感性有关。这个项目的目标是 是探索NFAT蛋白在调节IL-4基因中的不同作用 转录，并研究INFGamma基因表达的调节， 确定已知的多态是否影响INFGamma基因转录。 方案3：人气道平滑肌细胞因子(IL-4和IL-13)的反应 细胞。细胞因子IL-4和IL-13被认为在 过敏性哮喘的发展。这个项目的目标是具体地 探讨这些细胞因子在培养的人气道平滑肌中的作用 细胞。重要的是，已知的IL-4和IL-13基因多态性之间的相关性 将对受体进行寻址。项目4：调节IgE受体的表达 和功能。IgE/FceRI网络在变态反应中起核心作用 发炎。Ige调节FceRI的表达，进而调节FceRI的表达 中介效应器功能。这个项目的目标是剖析 特异性IgE介导的FceRI在分子水平的表达过程 强调了解受体β基因在这一过程中的作用 进程。具体地说，已知的β基因多态对 将被评估与哮喘和特应性疾病有关。总而言之， 基础科学项目与本SCOR中的临床部分相结合将 结果是加深了对有助于 哮喘的发病。希望这些联合调查在 这一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。

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.