Animal Core

特发性肺纤维化(IPF)是一种最神秘的致死性肺部疾病。尽管取得了重大进展 已经对IPF的发病机制、IPF发病的分子机制进行了深入的研究。 IPF的病理生理学仍知之甚少。此外，尽管两种抗纤维化药物吡非尼酮和 九替达尼已被FDA批准用于治疗IPF，这些药物的疗效为后期 这种疾病的死亡率尚不确定，而且两种药物都不能降低IPF的死亡率(1-4)。根据周期I的结果 在这个翻译计划项目(TPPG)中，我们将在这次更新中测试一个假设，即氧化还原-代谢 由先天/获得性免疫机制(肺泡巨噬细胞)调节的肌成纤维细胞激活的调控 和B细胞)，导致进行性纤维化。具体来说，我们将测试一种小分子的安全性和有效性 一项IIb期临床试验中的NOX1/4抑制剂(项目1；邓肯，项目负责人)并探讨其机制 通过NOX4调节Myo-FBS中的促纤维化代谢程序(项目2；Thanickal，项目负责人)。 基于新的令人信服的数据，我们还将研究NOX4在调节细胞代谢和 肺泡巨噬细胞的促纤维化表型(项目3；卡特，项目负责人)和自身抗体(B-Abs)的作用 细胞)在调节激活的myo-FBS中促纤维化基因的表观遗传控制(项目4；Sanders，项目 领袖)。为了帮助检验假说和开发治疗IPF的药物， 动物研究的核心是为建议的动物研究提供集中和标准化的程序 项目2、3和4。具体地说，核心将提供两种最常用的小鼠肺纤维化 项目2、3和4的模型，博莱霉素诱导的和石棉诱导的肺纤维化模型，以测试 GKT137831对肺纤维化的治疗作用及其机制。核心还将提供 规范口服给药服务(GKT137931)。此外，核心将提供 MicroCT图像和小鼠肺损伤和纤维化检测的标准化技术服务 FlexiVent肺功能检测。程序的集中化和标准化将带来高质量， 在各个项目之间取得可重复性和可比性的结果，这对本项目方案的成功至关重要。

Idiopathic pulmonary fibrosis (IPF) is a most enigmatic fatal lung disorder. Although significant progress has been made in our understanding of IPF pathogenesis, the molecular mechanisms underlying the pathophysiology of IPF remain poorly understood. Moreover, although two anti-fibrosis drugs, pirfenidone and nintedanib, have been approved by FDA for the treatment of IPF, the efficacy of these drugs for the later stages of the disease is uncertain and neither drug reduces IPF mortality (1-4). Based on the results from the Cycle I of this Translational Program Project (tPPG), we will, in this renewal tPPG, test a hypothesis that redox-metabolic control of myofibroblast activation, modulated by innate/adaptive immune mechanisms (alveolar macrophages and B-cells), leads to progressive fibrosis. Specifically, we will test the safety and efficacy of a small molecule inhibitor of NOX1/4 in a Phase IIb clinical trial (Project 1; Duncan, Project Leader) and explore the mechanisms by which NOX4 regulates pro-fibrotic metabolic programs in myo-Fbs (Project 2; Thannickal, Project Leader). Based on new convincing data, we will also investigate the role of NOX4 in regulating cellular metabolism and pro-fibrotic phenotypes of alveolar macrophages (Project 3; Carter, Project Leader) and the role of auto-Abs (B- cells) in regulating epigenetic control of pro-fibrotic genes in activated myo-Fbs (Project 4; Sanders, Project Leader). To aid in testing the hypothesis and developing the therapeutic drugs for IPF, the overall objective of the Animal Core is to provide centralized and standardized procedures for the animal studies proposed in Projects 2, 3, and 4. Specifically, the Core will provide two of the most commonly used murine lung fibrosis models, bleomycin-induced and asbestos-induced lung fibrosis models, for Project 2, 3, and 4 to test the therapeutic potential of GKT137831 for lung fibrosis and the underlying mechanism. The core will also provide standardized service for drug (GKT137931) delivery through oral gavage. Moreover, the Core will provide standardized technique service for the measurement of lung injury and fibrosis by micro CT image and mouse lung function by FlexiVent. Centralization and standardization of the procedures will lead to high quality, reproducible, and comparable results among individual projects, which are essential for the success of this tPPG.