Overlapping Airway Basal Cell Transcriptome Reprogramming in COPD and Lung Cancer

慢性阻塞性肺病和肺癌中重叠气道基底细胞转录组重编程

基本信息

批准号：
8641461
负责人：
RONALD G CRYSTAL
金额：
$ 83.49万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2011-06-15 至 2016-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Most cases of COPD and lung cancer are caused by cigarette smoking. Both diseases start in the airway epithelium, and COPD increases lung cancer risk 4.5-fold. Using airway epithelium genome-wide transcriptome analysis, we and others have concluded that smoking causes a field of molecular changes throughout the airway epithelium manifested by abnormal expression of genes/pathways relevant to COPD and lung cancer. In a paradigm shift from the strategy of assessing the entire differentiated airway epithelium to understand the disordered airway epithelial biology of COPD and lung cancer, this proposal focuses on airway basal cells (BC), the stem/progenitor cells from which the differentiated airway epithelium is derived. Our preliminary observations show that the BC transcriptome of smokers is markedly different from that of nonsmokers, it is a primitive, less differentiated transcriptome including human embryonic stem cell genes progressively up-regulated in COPD and lung cancer, it predicts lung cancer aggressiveness and survival, and is associated with a molecular phenotype of p53 inactivation. Therefore we hypothesize that smoking-dependent reprogramming of the BC transcriptome represents a common molecular pathogenetic mechanism of smoking-associated COPD and lung cancer, thus both "BC disorders," and that the BC transcriptome progressively adopts a cancer-like phenotype in smokers, in smokers with COPD and in the non-malignant airway epithelium of smokers with COPD with lung cancer. If correct, the consequence is a progressive inability of such reprogrammed BC to differentiate to a normal ciliated mucociliary epithelium. These studies should lead to identification of molecular pathways commonly altered in COPD and lung cancer vulnerable to therapeutic intervention to prevent or reverse the disordered BC transcriptome associated with these diseases. Aim 1 - using genome-wide gene expression profiling, assess the hypothesis that compared to healthy nonsmokers, the airway BC transcriptome of smokers, smokers with COPD and non-malignant epithelium of COPD smokers with lung cancer is progressively disordered and reprogrammed toward a common COPD and cancer-associated molecular phenotype. Aim 2 - examine the hypothesis that BC of smokers, smokers with COPD and non-malignant epithelium of COPD smokers with lung cancer progressively exhibit a defective capacity to differentiate into normal airway epithelium when placed on air-liquid interface culture but will generate progressively increasing numbers of colonies in clonogenic assays. Aim 3 - assess the hypothesis that by genetic/pharmacologic modulation of the abnormally expressed genes/pathways in the BC of smokers, COPD smokers and COPD smokers with lung cancer, will reverse their defective differentiation and self-renewal functions.

描述（由申请人提供）：大多数COPD和肺癌病例是由吸烟引起的。两种疾病都始于气道上皮，COPD增加了肺癌风险4.5倍。使用气道上皮基因组的转录组分析，我们和其他人得出结论，吸烟会导致整个气道上皮的分子变化领域，这是由于与COPD和肺癌相关的基因/途径异常表达所表现出的。在从评估整个分化气道上皮的策略中，以了解COPD和肺癌的无序气道上皮生物学的策略，该提案的重点是气道基底细胞（BC），茎/祖细胞从中得出了分化的气道上皮细胞。我们的初步观察表明，吸烟者的BC转录组与非吸烟者的转录组明显不同，它是一个原始的，较小的转录组，包括在COPD和肺癌中逐渐上调的人类胚胎干细胞基因，它预测肺癌的侵略性和存活率，并且与P53的分子现象型p53 iNctivivativativative。因此，我们假设BC转录组的吸烟依赖性重编程代表了与吸烟相关的COPD和肺癌的常见分子致病机制，因此两者都“ BC疾病”，BC转录组逐渐在吸烟者中，在吸烟者中，在非癌症的癌症中，在吸烟者中，癌症表型在吸烟者中采用了癌症表型。如果正确的话，其结果是该重编程的BC逐渐无法区分到正常的纤毛粘膜上皮。这些研究应导致鉴定在COPD和肺癌中通常改变的分子途径，这些途径容易受到治疗干预的影响，以防止或扭转与这些疾病相关的无序BC转录组。目的1-使用全基因组基因表达谱分析，评估与健康非吸烟者，吸烟者的气道转录组相比，患有COPD的吸烟者和非肺癌吸烟者的非机关性上皮的肺癌上皮，逐渐被逐渐失调，并且对普通COPD和癌症相关的分子现场进行了重新编程。 AIM 2-检查以下假设：吸烟者的BC，患有COPD的吸烟者和患有肺癌的COPD吸烟者上皮上皮逐渐表现出有缺陷的能力，可以分化为正常气道上皮，而当放置在空气中的界面培养上，但会逐渐增加克隆生理分析中的菌落数量。 AIM 3-评估以下假设：通过吸烟者，吸烟者和患有肺癌的COPD吸烟者的遗传/药理调节基因/途径异常表达的基因/途径，将逆转其缺陷的分化和自我更新功能。