Growth Factors and Signaling Pathways in PF

描述(由申请人提供)： 肺纤维化是一种病死率较高的特发性间质性肺疾病。该病的特点是实质内胶原的异常沉积，局部聚集成纤维细胞、肌成纤维细胞和年轻的结缔组织，发现于受影响肺内的独特位置。我们认为成纤维细胞对生长因子和细胞因子信号的异常反应是疾病进展的基础，可能是治疗的合适靶点和反应的标志。通过结合广泛的技术，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被识别出来，使用新的算法，每个样本可以分析数千个基因。组织微阵列将不仅测量相关基因产物的表达，还将测量反映对生长因子和细胞因子反应的信号，其中将在数百个组织样本中检测单个蛋白质。不同肺细胞间隔的激活状态将在患者和对照组中绘制地图，其定义方式以前在人类疾病的组织样本中是不可行的。反映成纤维细胞来源和对刺激反应的不同蛋白质的分泌将在体外进行，但也将利用支气管肺泡灌洗作为肺细胞分泌的窗口。提高产量和减少变异的新蛋白质组学技术将允许阐明反映疾病行为的BAL衍生蛋白质。其结果将是一组看似与过度的成纤维细胞对信号的反应有关的靶点，以及关于干预策略潜在成功的体外证据。将识别反映预后、病因学和治疗反应的新生物标记物，潜在地提高新试验的产量。这些数据应该会提高我们治疗和监测肺纤维化的能力。

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.