Allergen-driven epithelial genes in asthma pathogenesis

支气管哮喘是一种慢性肺部炎症性疾病， 在过去的几十年里，强调需要更好地了解疾病的分子基础。许多 实验、临床和遗传学研究表明，哮喘素质的发展依赖于 在CD 4 +T细胞产生Th 2细胞因子白细胞介素-13后。尽管作出了大量努力， IL-13介导的疾病的表现仍然是未知的。利用基因分析方法 为了鉴定IL-13的新下游靶点，我们已经鉴定了一组属于新描述的 几丁质酶家族（AMCase，YM-1），其在变应原和IL-13攻击的肺中高度上调 小鼠更重要的是，我们发现，在鼻息肉患者的鼻活检组织中，AMCase mRNA水平增加， 哮喘此外，人类中与哮喘相关的特征与1号染色体上含有哮喘相关基因的区域有关。 几丁质酶基因簇尽管事实上对几丁质酶基因的功能或它们的功能还一无所知， 在Th 2免疫应答中的确切作用它们已显示在多种炎性疾病中升高， 以诱导嗜酸性粒细胞炎症和趋化因子分泌，并直接诱导成纤维细胞生长。因此我们 计划对几丁质酶家族成员在哮喘发病机制中发挥重要作用的假设进行严格检验 AMCase基因的多态性可能与人类过敏性哮喘的发生有关。 具体目的是：1）研究AMCase和YM-1在IL-13诱导的细胞凋亡中的独特和/或重叠作用。 气道炎症和AHR的发展，通过调节它们的表达在体内利用几个 补充方法; 2）确定几丁质酶在过敏原诱导的上皮下纤维化中的作用， 小鼠，我们将评估组织纤维化，胶原蛋白的积累，并在体内产生促纤维化介质 和体外; 3）鉴定和表征编码几丁质酶的基因中潜在的功能多态性 家族成员，AMCase，在来自辛辛那提地区的两个特征良好的哮喘儿童队列中。 最后，我们将评估AMCase和IL-13及其受体IL-4 Ra之间的基因-基因相互作用。的力量 小鼠模型，以评估这些基因的功能作用， 在我们的人类队列中与哮喘/特应性相关的多态性将使我们对哮喘/特应性之间的关系有新的认识。 这些新的候选基因和特应性哮喘之间的联系，并使寻找新的治疗方法成为可能。

Bronchial asthma is a chronic inflammatory disorder of the lung that has reached epidemic proportions over the last few decades, underscoring the need fora better understanding of the molecular basis of disease. Numerous experimental, clinical and genetic studies suggest that the development of the asthmatic diathesis is dependent upon CD4+T cell production of the Th2 cytokine, interleukin-13. Despite intensive efforts, the mechanisms by which IL-13 mediates the manifestations of disease remain unknown. Utilizing a gene profiling approach to identify novel downstream targets of IL-13, we have identified a group of genes belonging to the newly described chitinase family (AMCase, YM-1), which are highly up-regulated in the lungs of allergen- and IL-13-challenged mice. Importantly, we find that AMCase mRNA levels are increased in nasal biopsies of from patients with asthma. Moreover, asthma-related traits in humans have been linked to regions of chromosome 1 containing the chitinase gene cluster. Although virtually nothing is known about the functions of the chitinase genes, or their exact roles in Th2 immune responses they have been shown to be elevated in a variety of inflammatory diseases, to induce eosinophilic inflammation and chemokine secretion, and to directly induce fibroblast growth. Thus, we plan to critically test the hypothesis that chitinase family members play an important role in asthma pathogenesis and that polymorphisms in the AMCase gene may contribute to the development of allergic asthma in humans. The specific aims are: 1) to investigate the unique and/or overlapping roles of AMCase and YM-1 in IL-13-induced airway inflammation and development of AHR, by modulating their expression in vivo utilizing several complementary approaches; 2) to determine the role of chitinases in allergen-induced sub-epithelial fibrosis in mice, we will assess tissue fibrosis, collagen accumulation, and the production of pro-fibrotic mediators in vivo and in vitro; 3) to identify and characterize potential functional polymorphisms in the gene encoding the chitinase family member, AMCase, in two well-characterized cohorts of asthmatic children from the Cincinnati region. Lastly, we will assess gene-gene interactions between AMCase and IL-13 and its receptor, IL-4Ra. The power of the murine model to assess the functional role of these genes in combination with identification of functional polymorphisms associated with asthma/atopy in our human cohorts will give us new insight into the relationship between these novel gene candidates and atopic asthma and empower the search for novel therapeutics.