"Neutrophil Elastase Links Idiopathic Pulmonary Fibrosis and Lung Cancer"

“中性粒细胞弹性蛋白酶与特发性肺纤维化和肺癌有关”

基本信息

批准号：
8158662
负责人：
A McGarry Houghton
金额：
$ 37.1万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8158662
关键词：
1-Phosphatidylinositol 3-Kinase Accounting Adenocarcinoma Alveolar American Asbestos Asbestos-related lung injury Automobile Driving Behavior Binding Biochemical Cancer Etiology Cell Proliferation Cell Surface Receptors Cell membrane Cell surface Cells Cessation of life Characteristics Chronic Obstructive Airway Disease Chronic lung disease Clathrin Data Development Disease Disease Progression Disease model Distant E-Cadherin Endocytosis Endosomes Enzymes Epithelial Fibroblasts Fibrosis Grant Hamman-Rich syndrome Hyperplasia Inflammatory Joints Leukocyte Elastase Link Lung Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Mesenchymal Modeling Movement Mus Myofibroblast N-Cadherin National Heart, Lung, and Blood Institute Nature Neoplasm Metastasis Organ Outcome Pathway interactions Patients Peptide Hydrolases Phenotype Process Production Proteins Pulmonary Fibrosis Reporting Risk Serine Protease Therapeutic adenoma advanced disease antimicrobial drug cancer cell cell behavior design epithelial to mesenchymal transition expression cloning in vivo insulin receptor substrate 1 protein mortality mouse model neoplastic cell neutrophil neutrophil elastase inhibitor new therapeutic target novel receptor research study therapeutic target tumor tumor growth

项目摘要

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.

描述（由申请人提供）：肺癌和特发性肺纤维化（IPF）是连接的疾病，IPF患者患肺癌的风险增加了7倍。这两种疾病的特征都以惨淡的患者结局和缺乏有效疾病修饰疗法的特征。鉴定常见疾病进展的物质可能会产生新的治疗靶标。我们建议中性粒细胞衍生的丝氨酸蛋白酶中性粒细胞弹性酶（NE）就是这样的靶标。 NE通过相似的机制在小鼠模型中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，肿瘤细胞和成纤维细胞的靶细胞。首先，NE诱导肿瘤细胞和成纤维细胞增殖。其次，NE改变了肿瘤细胞和成纤维细胞的行为，从而产生肿瘤细胞上皮到间质转变（EMT），并驱动肌纤维细胞分化。在肺癌和IPF的情况下，这两个过程都与晚期疾病密切相关。该建议将确定NE诱导细胞增殖并改变细胞行为的机制，以期确定两种疾病常见的新型治疗靶标。此外，这些研究应验证NE本身，作为对肺癌和/或IPF造成的患者的有效治疗靶标。公共卫生相关性：肺癌和特发性肺纤维化是“联系”，疾病的，这意味着IPF患者随后患肺癌的风险增加。这两种疾病的结果都是令人沮丧的，每年的死亡率均达到了近200,000次。我们已经确定了一种称为中性粒细胞弹性蛋白的炎性细胞得出的蛋白质，该蛋白质促进IPF和肺癌的疾病进展。该提案的目的是为肺癌和/或肺纤维化患者建立中性粒细胞弹性蛋白酶作为合法的治疗靶标。