Animal Core

动物核心

• 批准号: 10218249
• 负责人: RUI-MING LIU
• 金额: $ 19.75万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218249
• 关键词: Age; Alveolar Macrophages; Animal Genetics; Animals; Asbestos; B-Lymphocytes; Basic Science; Bleomycin; Clinical Trials; Data; Disease; Drug Delivery Systems; Epigenetic Process; Evaluation; FDA approved; Fibrosis; Functional disorder; Genes; Gold; Immune; Individual; Laboratories; Lung; Lung diseases; Measurement; Metabolic; Metabolic Control; Metabolism; Modeling; Molecular; Mus; Myofibroblast; NADPH Oxidase 1; Oral; Oxidation-Reduction; Pathogenesis; Pharmaceutical Preparations; Phase; Phenotype; Physicians; Physiology; Pirfenidone; Procedures; Pulmonary Fibrosis; Reproducibility; Research Personnel; Rodent; Role; Services; Standardization; System; Techniques; Testing; Therapeutic; X-Ray Computed Tomography; base; drug efficacy; experience; high resolution imaging; idiopathic pulmonary fibrosis; imaging modality; in vivo; instrument; lung injury; microCT; mortality; programs; pulmonary function; safety testing; sex; small molecule inhibitor; success; therapeutic evaluation; therapeutic target; therapeutically effective

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.

特发性肺纤维化（IPF）是最神秘的致命肺疾病。虽然取得了重大进展 在我们对IPF发病机理的理解中，已经制作了分子机制 IPF的病理生理学知之甚少。此外，尽管两种抗纤维化药物，吡啶酮和 Nintedanib已获得FDA的批准用于治疗IPF，这些药物在后期的疗效 该疾病不确定，两种药物都不降低IPF死亡率（1-4）。根据周期I的结果 在这个翻译计划项目（TPPG）中，我们将在此续签TPPG中测试氧化还原代谢的假设 通过先天/适应性免疫机制调节肌纤维细胞激活（肺泡巨噬细胞） 和B细胞），导致进行性纤维化。具体而言，我们将测试小分子的安全性和功效 IIB期临床试验中NOX1/4的抑制剂（项目1；项目负责人Duncan）并探索机制 NOX4在Myo-FBS中调节促纤维化代谢程序（项目2；项目负责人Thannickal）。 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（项目3; Carter，Project Leader）的促纤维化表型和自动ABS的作用（B- 细胞）调节激活的肌fb的促纤维基因的表观遗传控制（项目4；桑德斯，项目 领导者）。为了帮助测试假设并开发IPF的治疗药物，这是 动物核心将为提出的动物研究提供集中和标准化的程序 项目2、3和4。具体来说，核心将提供两个最常用的鼠肺纤维化 博来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 GKT137831对肺纤维化和潜在机制的治疗潜力。核心也将提供 药物标准化服务（GKT137931）通过口服饲料提供。而且，核心将提供 通过微CT图像和小鼠测量肺损伤和纤维化的标准化技术服务 肺部功能通过屈曲。程序的集中和标准化将导致高质量， 单个项目之间可再现和可比较的结果，这对于该TPPG的成功至关重要。