Growth Factors and Signaling Pathways in Pulmonary Fibr*

肺纤维中的生长因子和信号通路*

• 批准号: 6922075
• 负责人: George SCOTT WORTHEN
• 金额: $ 64.48万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-19 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6922075
• 关键词: apoptosis; biological signal transduction; biomarker; bronchoscopy; cell proliferation; clinical research; fibroblasts; gene expression; growth factor receptors; high throughput technology; human middle age (35-64); human old age (65+); human subject; immunocytochemistry; lung lavage; microarray technology; pathologic process; proteomics; pulmonary fibrosis /granuloma; transforming growth factors

DESCRIPTION (provided by applicant): Pulmonary fibrosis is an idiopathic interstitial lung disease with high mortality. The illness is characterized by abnormal intraparenchymal deposition of collagen, with focal accumulations of fibroblasts, myofibroblasts and young connective tissue that are found in unique locations within the affected lung. We propose that aberrant responses of fibroblasts to growth factor and cytokine signaling underlie the progression of disease, and may represent appropriate targets for therapy and markers of response. Using a combination of broadbased techniques, the gene expression patterns of lungs and fibroblasts from patients with pulmonary fibrosis and controls will be discerned using novel algorithms allowing analysis of many thousands of genes per sample. Expression not only of relevant gene products but also signals reflecting response to growth factors and cytokines will be measured in tissue microarrays, where a single protein will be examined in hundreds of tissue samples. The activation state of distinct lung cellular compartments, defined in a fashion not previously feasible in tissue samples from human disease, will be mapped in patients and controls. The secretion of distinct proteins that reflect fibroblast origin and response to stimulation will be pursued both in vitro, but also using bronchoalveolar lavage as a window on secretion by lung cells. New proteomic techniques to enhance throughput and reduce variation will allow elucidation of BAL-derived proteins that reflect disease behavior. The result will be a set of targets plausibly involved in excessive fibroblastic response to signals, and in vitro evidence as to the potential success of intervention strategies. New biomarkers reflecting prognosis, nosology, and response to therapy will be discerned, potentially improving the yield of new trials. The data should advance our ability to treat and monitor pulmonary fibrosis.

描述（由申请人提供）： 肺纤维化是一种病死率高的特发性间质性肺病。该疾病的特征在于胶原蛋白的异常实质内沉积，以及在受影响的肺内的独特位置中发现的成纤维细胞、肌成纤维细胞和年轻结缔组织的局灶性积聚。我们认为成纤维细胞对生长因子和细胞因子信号传导的异常反应是疾病进展的基础，并可能代表适当的治疗靶点和反应标志物。使用广泛基础的技术的组合，肺纤维化患者和对照组的肺和成纤维细胞的基因表达模式将使用新的算法来识别，从而允许每个样本分析数千个基因。不仅相关基因产物的表达，而且反映对生长因子和细胞因子的反应的信号也将在组织微阵列中测量，其中将在数百个组织样品中检查单个蛋白质。将在患者和对照组中绘制不同肺细胞区室的激活状态，该激活状态以先前在人类疾病组织样本中不可行的方式定义。反映成纤维细胞来源和对刺激的反应的不同蛋白质的分泌将在体外进行，但也使用支气管肺泡灌洗作为肺细胞分泌的窗口。新的蛋白质组学技术，以提高吞吐量和减少变异将允许阐明BAL-derived蛋白质，反映疾病的行为。结果将是一组可能参与过度成纤维细胞对信号的反应的靶点，以及关于干预策略潜在成功的体外证据。反映预后、疾病分类学和治疗反应的新生物标志物将被发现，这可能会提高新试验的产量。这些数据将提高我们治疗和监测肺纤维化的能力。