IMMUNOGENETIC DISEASE-ALLERGIC INFLAMMATION TO AIRWAY REMODELING IN ASTHMA

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这一开发项目的总体目标是了解亚洲人和太平洋岛民哮喘易感性的遗传决定因素，并评估这种易感性对呼吸道重塑的影响。具体地说，我们将在我们的哮喘患者中检验以下假设：1.编码白细胞介素4(IL-4)受体和白细胞介素10(IL-10)启动子的阿尔法链的基因的变异与T辅助细胞2型(Th2)应答增加有关，Th2应答是哮喘的一种特异性炎症反应。2.Th2途径的激活与参与成纤维细胞/肌成纤维细胞增殖和激活的基因的差异转录有关，从而导致气道重塑。3.这些基因的产物在有呼吸道重塑功能证据的哮喘受试者的呼吸道细胞和组织中差异表达。这些假说将通过实现以下特定目标来探索：特定目标1：与非过敏性哮喘和哮喘患者相比，确定过敏性哮喘和气道重塑患者循环白细胞中转录水平最高的细胞因子和生长因子基因。具体目的2：阐明IL-4受体α和IL-10启动子基因变异之间的关系，并检测哮喘和非哮喘患者Th2途径的激活情况。特异性目标3：鉴定在人呼吸道成纤维细胞系和原代培养的人鼻成纤维细胞中参与胶原和其他基质蛋白形成的基因的基线表达。特异性目标4：鉴定和确认编码细胞外基质蛋白或细胞凋亡相关基因的基因对特异性目标1中确定的细胞因子的转录反应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goals of this developmental project are to understand the genetic determinants of susceptibility to asthma among Asians and Pacific Islanders and to evaluate the consequences of this susceptibility on airway remodeling. Specifically, we will examine in our population of asthmatics the following hypotheses: 1. Variant polymorphisms in the genes which encode the alpha chain of the interleukin 4 (IL-4) receptor and the interleukin 10 (IL-10) promoter are associated with increased T-helper type 2 (Th2) response, which is a specific inflammatory response to asthma. 2. Activation of the Th2 pathway is associated with differential transcription of genes implicated in fibroblast/myofibroblast proliferation and activation, leading to airway remodeling. 3. Products of these genes are differentially expressed in airway cells and tissues of asthmatic subjects who have functional evidence of airway remodeling. These hypotheses will be explored by fulfilling the following specific aims: Specific aim 1: Identify cytokine and growth factor genes that are most highly expressed at the transcriptional level in circulating leukocytes of patients with allergic asthma and airway remodeling, compared to patients who are neither allergic nor asthmatic. Specific aim 2: Elucidate the association between variants in the IL-4 receptor alpha and IL-10 promoter genes and measure the activation of the Th2 pathway in asthmatic and non-asthmatic patients. Specific aim 3: Characterize the baseline expression of genes involved in the formation of collagen and other matrix proteins in cultures of human airway fibroblast cell lines and primary cultures of human nasal fibroblasts Specific aim 4: Characterize and confirm the transcriptional response of genes that encode extracellular matrix proteins or apoptosis-related genes to cytokines identified in specific aim 1.