Animal Core

特发性肺纤维化（IPF）是一种最神秘的致命性肺部疾病。虽然取得了重大进展， 我们对IPF发病机制的理解已经取得了进展， IPF的病理生理学仍然知之甚少。此外，尽管两种抗纤维化药物吡非尼酮和 尼达尼布已被FDA批准用于治疗IPF，这些药物对晚期的疗效 该病的发病率尚不确定，两种药物均不能降低IPF死亡率（1-4）。根据周期I的结果， 本翻译计划项目（tPPG），我们将，在此更新tPPG，测试一个假设，即氧化还原代谢 控制肌成纤维细胞活化，由先天性/适应性免疫机制（肺泡巨噬细胞）调节 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， 在IIb期临床试验（项目1;邓肯，项目负责人）中使用NOX 1/4抑制剂，并探索其机制 NOX 4通过其调节myo-Fbs中的促纤维化代谢程序（项目2; Thannickal，项目负责人）。 基于新的令人信服的数据，我们还将研究NOX 4在调节细胞代谢中的作用， 肺泡巨噬细胞的促纤维化表型（项目3; Carter，项目负责人）和自身抗体（B- 细胞）调节活化肌纤维蛋白原中促纤维化基因的表观遗传控制（项目4; Sanders，项目 Leader）。为了帮助检验这一假设并开发IPF的治疗药物， 动物中心将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。具体而言，核心将提供两种最常用的鼠肺纤维化 模型，博莱霉素诱导的和石棉诱导的肺纤维化模型，用于项目2、3和4，以测试 GKT 137831对肺纤维化的治疗潜力和潜在机制。核心还将提供 口服灌胃给药（GKT 137931）标准化服务。此外，核心将提供 肺损伤和肺纤维化的显微CT图像和小鼠测量标准化技术服务 肺功能检查。程序的集中化和标准化将带来高质量， 在各个项目中获得可重复和可比较的结果，这对于tPPG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.