Molecular Mechanisms Leading to Human Asthma

描述（申请人的摘要） 哮喘是一种慢性炎症综合征，其常见的病理生物学特征是 表现就是炎症。哮喘的病因尚不清楚， 人们普遍认为哮喘是由两者之间的相互作用引起的 环境和遗传因素。然而，人们对于基因的了解却知之甚少。 有助于哮喘。该 SCOR 的目标是使用遗传方法 识别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。拟议的哮喘 SCOR 包括四项科学内容 项目，其中一个项目作为临床部分。每一个 这些项目将剖析与人类相关的途径 哮喘并将功能评估已经存在的基因多态性 已确定可能影响这些途径。项目 1：精细测绘，以及 候选基因的测试。该项目的目标是精细绘制哮喘地图 12Q上的候选基因并为项目提供基于人群的资源 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 INFgamma）基因表达的调节。细胞因子 IL-4 和INFgamma 都在哮喘的发展中起着关键作用。 重要的是，INFgamma 基因内含子区域的多态性 与哮喘的遗传倾向有关。该项目的目标 旨在探讨NFAT蛋白在调节IL-4基因中的不同作用 转录并研究 INFgamma 基因表达的调控， 确定已知的多态性是否影响 INFgamma 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 被认为在 过敏性哮喘的发展。该项目的目标是专门 解决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 受体将得到解决。项目4：IgE受体表达的调控 和功能。 IgE/FceRI 网络在过敏反应中起核心作用 炎症。 IgE 调节 FceRI 表达蛋白，而 FceRI 表达蛋白又调节 FceRI 介导的效应器功能。该项目的目标是剖析 IgE 介导的 FceRI 在分子水平上表达的过程 重点是了解受体β基因在此过程中的作用 过程。具体来说，β 基因中已知多态性的影响 与哮喘相关并且将评估过敏性。综合起来， SCOR 中的基础科学项目与临床部分相结合 从而加深对有助于实现这一目标的机制的了解 哮喘病的发作。希望这些联合调查能够 该 SCOR 将为进一步的基因发现和功能性研究提供一个平台。 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.