IMMUNOGENETIC DISEASES-ALLERGIC INFLAMMATION TO AIRWAY REMODELING IN ASTHMA

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这个发展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气道重塑的影响。 具体来说，我们将在我们的哮喘患者人群中研究以下假设： 1.编码白细胞介素4（IL-4）受体α链和白细胞介素10（IL-10）启动子的基因中的变异多态性与增加的辅助性T细胞2型（Th 2）应答相关，这是对哮喘的特异性炎症应答。 2. Th 2途径的激活与涉及成纤维细胞/肌成纤维细胞增殖和激活的基因的差异转录相关，导致气道重塑。 3.这些基因的产物在具有气道重塑的功能证据的哮喘受试者的气道细胞和组织中差异表达。 将通过实现以下具体目标来探讨这些假设： 具体目标1：与既不过敏也不哮喘的患者相比，识别过敏性哮喘和气道重塑患者循环白细胞中转录水平最高表达的细胞因子和生长因子基因。 具体目标2：阐明IL-4受体α和IL-10启动子基因变体之间的关联，并测量哮喘和非哮喘患者中Th 2通路的激活。 具体目标3：表征人气道成纤维细胞系培养物和人鼻成纤维细胞原代培养物中参与胶原蛋白和其他基质蛋白形成的基因的基线表达 具体目标4：表征并确认编码细胞外基质蛋白或糖尿病相关基因的基因对特定目的1中鉴定的细胞因子的转录应答。

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.