Targeting epithelial cells to treat pulmonary fibrosis

靶向上皮细胞治疗肺纤维化

• 批准号: 8338919
• 负责人: Dean Sheppard
• 金额: $ 259.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-09 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338919
• 关键词: Address; Alveolar; Alveolar Macrophages; Apoptosis; Biological Markers; Blood; Blood specimen; Bronchoalveolar Lavage Fluid; Cells; Chemistry; Clinical Trials; Development; Drug Delivery Systems; Effectiveness; Epithelial; Epithelial Cells; Fibrosis; Grant; Hamman-Rich syndrome; Human; Integrin beta Chains; Integrins; Liquid substance; Lung; Mediating; Mus; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Program Research Project Grants; Proteins; Pulmonary Fibrosis; Reading; Reproducibility; Signal Transduction; Site; Stress; Tissues; Toxic effect; Transforming Growth Factor beta; Work; base; cohort; design; drug candidate; drug efficacy; effective therapy; extracellular; improved; mouse model; novel; pre-clinical; programs; response

DESCRIPTION: This translational program project grant is designed to develop new effective therapies for idiopathic pulmonary fibrosis (IPF). The grant is entirely focused on developing new drugs that specifically target known pathways in alveolar epithelial cells that are critical fo the development of pulmonary fibrosis. The grant will also use a novel, mechanism-based approach to identify informative biomarkers from human cells and tissues that should provide early indicators of the effectiveness of each of the drugs we develop in subsequent early phase clinical trials in patients with IPF. The rationale for this grant is that IPF is a consequence of n-going epithelial stress and apoptosis, which leads to activation of extracellular latent TGFbeta by the alpha nu beta integrin on alveolar epithelial cells, which in turn induces progressive fibrosis at least in part through induction of TGFbeta signaling in epithelial cells. The proposal includes 3 projects which will each utilize multiple mouse models of pulmonary fibrosis to evaluate the efficacy of existing drug agents that target apoptosis induced by the unfolded protein response, integrin-mediated TGFbeta activation and TGFbeta signaling in epithelial cells, and to develop novel agents with improved potency and reduced systemic toxicity. By parallel analysis of the effects of these drug agents on human alveolar epithelail cells and human lung fragments, these projects will further asess the applicability of murine findings to humans. Each project will also take advantage of serial samples of blood and BAL cells and fluid from patients with IPF and healthy controls to characterize the utiltiy and reproducibility of putative biologically informative biomarkers. These projects will be supported by a human lung cell and tissue core, a longitudinal cohort core, a mediciinal chemistry core and a centralized administrative core. By performing extenisve pre-clinical analysis of the most promising candidate drugs, establishing their effectiveness in human lung, and developing read-outs of drug effectiveness that can be detected in blood, bronchoalveolar lavage fluid or alveolar macrophages, the work performed should lay the groundwork for clinical trials of the most promising candidates in a planned second phase of this program.

描述：该转化计划项目拨款旨在开发治疗特发性肺纤维化（IPF）的新有效疗法。该拨款完全专注于开发新药，专门针对肺泡上皮细胞中已知的通路，这些通路对肺纤维化的发展至关重要。该赠款还将使用一种新颖的、基于机制的方法来识别来自人体细胞和组织的信息丰富的生物标志物，这些生物标志物应该为我们在 IPF 患者的后续早期临床试验中开发的每种药物的有效性提供早期指标。此项资助的基本原理是，IPF 是持续上皮应激和细胞凋亡的结果，这导致肺泡上皮细胞上的 alpha nu beta 整联蛋白激活细胞外潜在的 TGFbeta，进而至少诱导进行性纤维化 部分是通过诱导上皮细胞中的 TGFbeta 信号传导。该提案包括 3 个项目，每个项目将利用多种肺纤维化小鼠模型来评估现有药物制剂的功效，这些药物制剂针对上皮细胞中未折叠蛋白反应、整合素介导的 TGFbeta 激活和 TGFbeta 信号传导诱导的细胞凋亡，并开发新药物具有提高的效力和降低的全身毒性。通过平行分析这些药物对人类肺泡上皮细胞和人类肺碎片的影响，这些项目将进一步评估小鼠研究结果对人类的适用性。每个项目还将利用来自 IPF 患者和健康对照的血液和 BAL 细胞以及液体的系列样本来表征假定的具有生物学信息的生物标志物的效用和再现性。这些项目将得到人类肺细胞和组织核心、纵向队列核心、药物化学核心和集中管理核心的支持。通过对最有前途的候选药物进行广泛的临床前分析，确定它们在人肺中的有效性，并开发可在血液、支气管肺泡灌洗液或肺泡巨噬细胞中检测到的药物有效性读数，所做的工作应该奠定基础在该计划计划的第二阶段对最有希望的候选人进行临床试验。