Genetic Role of EGFR pathway in Interstitial Lung Disease

描述(由申请人提供)： 背景：间质性肺病(ILD)包括广泛的慢性肺部疾病。该病的发病机制大多尚不清楚。人们普遍认为遗传因素在间质性肺病(ILD)的发生发展中起着重要作用。然而，目前还没有发现常见实体的可检测等位基因。最近，表皮生长因子受体(EGFR)抑制剂的应用被证明在肺癌患者中诱导ILD，具有显著的种族差异。这一观察结果和来自基因工程动物模型的证据相结合，表明与EGFR相关的基因变异有助于ILD的发展。我们的最终目标是通过了解EGFR的调控及其通过遗传多态性传递的信号来确定ILD的遗传决定因素。我们已经在EGFR途径基因中发现了功能性遗传变异。我们推测，EGFR途径基因中的这些遗传变异可能决定了基因的表达，并调节了人肺中的EGFR信号，从而增加了ILD的易感性。为了验证我们的假设，我们提出了利用肺组织研究联盟(LTRC)收集的大量疾病样本进行研究。具体目的：1)进行基于群体的EGFR途径基因功能变异与ILD的相关性研究；2)评价ILD组织中EGFR途径功能变异与基因表达的相关性；3)检测不同细胞类型ILD组织中功能变异与EGFR信号活性之间的相互作用。意义：这项研究有可能确定人类ILD的遗传风险因素，并提供对该疾病发病机制的重要洞察。公共卫生相关性：项目叙述这项研究将测试一组与表皮生长因子受体(EGFR)相关的基因内的基因变异是否会增加患间质性肺病(ILD)的风险。了解这一点可能有助于识别未来可能患上这种疾病的人，从而有可能预防这种疾病。它还将有助于确定可用于开发更好的ILD治疗方法的分子靶点。(摘要结束)

DESCRIPTION (provided by applicant): Background: Interstitial lung disease (ILD) encompasses a broad range of chronic lung disorders. The mechanisms of pathogenesis for the development of this disease are mostly unknown. It is widely believed that genetic factors play an important role in the development of interstitial lung disease (ILD). However, testable alleles accounting for common entities have not yet been discovered. Recently, administration of inhibitors for epidermal growth factor receptor (EGFR) has been shown to induce ILD in lung cancer patients with significant ethnic differences. The combination of this observation and evidence from genetically engineered animal models suggests that genetic variation related to EGFR contributes to the development of ILD. Our ultimate goal is to identify the genetic determinants of ILD through understanding the regulation of EGFR and its signaling by genetic polymorphisms. We have identified functional genetic variants in EGFR pathway genes. We hypothesize that these genetic variants in EGFR pathway genes may determine gene expression and modulate EGFR signaling in human lung, thus conferring susceptibility to ILD. To test our hypothesis, we propose studies utilizing the large disease sample collection from The Lung Tissue Research Consortium (LTRC). Specific Aims: 1) To conduct a population-based association study between functional variants in EGFR pathway genes and ILD; 2) To evaluate the correlation between the functional variants and gene expression of the EGFR pathway in ILD tissue; 3) To test the interaction between the functional variants and EGFR signaling activity in different cell types of ILD tissue. Significance: This investigation has the potential to identify the genetic risk factors of human ILD, and to provide insight into mechanisms important to the pathogenesis of the disease. PUBLIC HEALTH RELEVANCE: Project Narrative This study will test whether genetic variants within a group of genes related to the epidermal growth factor receptor (EGFR) increase the risk to develop interstitial lung disease (ILD). Understanding this could potentially help to identify the individuals who may develop the disease in the future and thus potentially prevent it. It will also help to identify molecular targets that could be used to develop better treatment for ILD. (End of Abstract)