"Neutrophil Elastase Links Idiopathic Pulmonary Fibrosis and Lung Cancer"

描述（由申请人提供）：肺癌和特发性肺纤维化（IPF）是相关疾病，IPF患者患肺癌的风险增加了7倍。这两种疾病的特点都是患者预后不佳，缺乏有效的疾病治疗方法。常见疾病进展物质的鉴定可能产生新的治疗靶点。我们认为中性粒细胞衍生的丝氨酸蛋白酶，中性粒细胞弹性蛋白酶（NE）就是这样一个靶点。在小鼠模型中，NE通过相似的机制驱动肺腺癌和肺纤维化的疾病进展。NE分别以两种不同的方式影响癌症和纤维化的靶细胞，即肿瘤细胞和成纤维细胞。首先，NE诱导肿瘤细胞和成纤维细胞增殖。其次，NE改变肿瘤细胞和成纤维细胞的行为，产生肿瘤细胞上皮向间充质转化（EMT），并驱动肌成纤维细胞分化。这两个过程都与肺癌和IPF的晚期疾病密切相关。该建议将确定NE诱导细胞增殖和改变细胞行为的机制，以期确定两种疾病共同的新治疗靶点。此外，这些研究应该验证NE本身作为肺癌和/或IPF患者的有效治疗靶点。

DESCRIPTION (provided by applicant): Lung cancer and idiopathic pulmonary fibrosis (IPF) are linked diseases, with IPF patients being at a seven-fold increased risk of lung cancer. Both of these diseases can be characterized by dismal patient outcomes and the lack of effective disease modifying therapies. The identification of common disease progressing substances may yield novel therapeutic targets. We propose that the neutrophil-derived serine proteinase, neutrophil elastase (NE), is such a target. NE drives disease progression of both lung adenocarcinoma and lung fibrosis in mouse models via similar mechanisms. NE impacts the target cell in cancer and fibrosis, the tumor cell and fibroblast, respectively, in two distinct ways. First, NE induces tumor cell and fibroblast proliferation. Second, NE alters the behavior of tumor cells and fibroblasts, generating tumor cell epithelial to mesenchymal transition (EMT), and driving myofibroblast differentiation. Both of these processes are intimately linked to advanced disease in the setting of lung cancer and IPF. This proposal will identify the mechanisms by which NE induces cell proliferation and alters cell behavior in hopes to identify novel therapeutic targets common to both diseases. Additionally, these studies should validate NE itself, as a valid therapeutic target for patients inflicted with lung cancer and/or IPF. PUBLIC HEALTH RELEVANCE: Lung cancer and idiopathic pulmonary fibrosis are "linked," diseases, meaning that patients with IPF are at an increased risk to subsequently develop lung cancer. The outcomes for both of these diseases are dismal, with combined mortality reaching nearly 200,000 American lives each year. We have identified an inflammatory cell derived protein called neutrophil elastase that promotes disease progression in both IPF and lung cancer. The purpose of this proposal is to establish neutrophil elastase as a legitimate therapeutic target for patients with lung cancer and/or pulmonary fibrosis.