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）包括一系列慢性肺部疾病。这种疾病发展的发病机制大多是未知的。目前普遍认为遗传因素在间质性肺疾病（ILD）的发生发展中起重要作用。然而，尚未发现可测试的等位基因占共同的实体。最近，表皮生长因子受体（EGFR）抑制剂的给药已被证明可诱导肺癌患者的ILD，具有显著的种族差异。这一观察结果与来自基因工程动物模型的证据相结合表明，EGFR相关的遗传变异有助于ILD的发生。我们的最终目标是通过了解EGFR及其信号转导的遗传多态性来确定ILD的遗传决定因素。我们已经确定了EGFR通路基因的功能性遗传变异。我们假设EGFR通路基因中的这些遗传变异可能决定人肺中的基因表达并调节EGFR信号传导，从而赋予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）的大型疾病样本收集的研究。 具体目标：1）开展基于人群的EGFR通路基因功能变异与ILD的关联研究; 2）评价ILD组织中EGFR通路基因功能变异与基因表达的相关性; 3）检测ILD组织中不同细胞类型中EGFR通路基因功能变异与EGFR信号活性的相互作用。 重要性：这项研究有可能确定人类ILD的遗传风险因素，并深入了解疾病发病机制的重要性。公共卫生相关性：本研究将检测一组与表皮生长因子受体（EGFR）相关的基因内的遗传变异是否会增加间质性肺病（ILD）的风险。了解这一点可能有助于识别未来可能发生这种疾病的个体，从而有可能预防这种疾病。它还将有助于识别可用于开发更好的ILD治疗方法的分子靶点。 (End摘要）

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)