SCOR in Pathobiology of Fibrotic Lung Disease

(申请人摘要)这项条例草案的长远目标是推动我们的 对特发性间质性肺炎发病机制的认识 (向上)。需要对这些疾病的发病机制有一个清楚的了解。 开发新的治疗策略。这一SCOR的中心假设 建议是：在效应器分子的精加工中或在 炎性细胞、上皮细胞和间充质细胞受体的表达 创造有利于纤维增生剂的肺泡微环境 反应，而不是正常的修复。这种自我分泌和/或调节失调 旁分泌调节环路决定易感性和表达 纤维性肺病。在这个SCOR的每个项目中，这个中心假设 将被扩展以定义一组特定调解人和/或 与纤维化相关的病理生物学过程中的受体。这些 介体包括细胞因子、趋化因子、类淀粉和蛋白水解酶。研究 将利用纤维化动物模型和/或幽门螺杆菌患者来检查 细胞和组织中的异常及其在细胞和组织中的作用 纤维化的病理生物学。一个重要的特点是机械性的洞察力 这些研究为标准(泼尼松、硫唑嘌呤)的使用提供了依据 强的松)和新型(5-脂氧合酶抑制剂，齐留通)治疗药物 在我们正在进行的临床项目中进行调查。 这项SCOR将采取多学科方法来检验这些假说。 接受过内科、病理学、细胞学培训的研究人员的专业知识 并将利用分子生物学、生物化学和生物统计学。这个 这项提议的优点是调查人员长期以来对 纤维性肺病，双方合作研究的已被证明的承诺 临床医生和基础科学家，接触到大量的IIP患者， 和非凡的生物医学研究机构资源。此SCOR 利用从长椅到床边的连续研究，这对 将基础研究的进展转化为临床领域。

(Applicant's Abstract) The long-term objective of this SCOR is to further our understanding of the pathogenesis of the idiopathic interstitial pneumonias (UP). A clear understanding of the pathogenesis of these diseases is required to develop new treatment strategies. The central hypothesis for this SCOR proposal is: Local alterations in the elaboration of effector molecules or in the expression of receptors by inflammatory, epithelial, and mesenchymal cells create an alveolar microenvironment that favors the fibroproliferative response rather than normal repair. Such dysregulation in autocrine and/or paracrine regulatory loops determine susceptibility to and expression of fibrotic lung disease. In each project of this SCOR, this central hypothesis will be extended to define the role of a specific set of mediators and/or receptors in pathobiological processes relevant to fibrogenesis. These mediators include cytokines, chemokines, elcosanoids and proteases. Studies will utilize animal models of fibrosis and/or patients with HP to examine abnormalities in cells and tissues and the role of each mediator in the pathobiology of fibrosis. An important feature is the mechanistic insights these studies provide to the use of standard (prednisone, azathioprine + prednisone) and novel (5-lipoxygenase inhibitor, zileuton) therapeutic agents under investigation in our ongoing clinical project. This SCOR will take a multi-disciplinary approach to testing these hypotheses. The expertise of investigators trained in Internal Medicine, Pathology, Cell and Molecular Biology, Biochemistry, and Biostatistics will be utilized. The strength of this proposal are the investigators long-standing interests in fibrotic lung disease, a proven commitment to collaborative research by both clinicians and basic scientists, access to a large population of IIP patients, and extraordinary institutional resources of biomedical Research. This SCOR capitalizes on a bench to bedside continuum of research that is crucial to translate advances in basic research to the clinical arena.