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：此翻译计划项目赠款旨在开发针对特发性肺纤维化（IPF）的新有效疗法。该赠款完全专注于开发新药物，这些新药是针对肺泡上皮细胞中已知途径的新药，这对肺纤维化的发展至关重要。该赠款还将使用一种基于机制的新方法来鉴定来自人类细胞和组织的信息性生物标志物，这些生物标志物应提供早期指标，说明我们在随后的IPF患者的早期早期临床试验中开发的每种药物的有效性。该赠款的基本原理是IPF是N-进行N-进行N-的上皮压力和凋亡的结果，这导致alpha nu beta beta整合素在肺泡上皮细胞上激活细胞外潜在TGFBETA，这反过来又诱导了渐进纤维化 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，每个项目都将使用多种肺纤维化的小鼠模型来评估现有药物的疗效，这些药物的功效是由展开的蛋白质反应引起的凋亡，整联蛋白介导的TGFBETA激活和TGFBETA信号在上皮细胞中的TGFBETA激活以及具有不良耐药性和降低系统毒性的新颖性的效果。通过对这些药物对人肺泡上皮细胞和人肺碎片的影响的平行分析，这些项目将进一步提高鼠类发现对人类的适用性。每个项目还将利用IPF和健康对照患者的血液和BAL细胞的系列样本，以表征假定的生物学上有用的生物标志物的实用性和可重复性。这些项目将得到人类肺部细胞和组织核的支持，纵向队列核心，药物化学核心和集中的行政核心。通过对最有前途的候选药物进行临床前分析，确定其在人肺中的有效性，并开发出可以在血液，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的读数，应为在该计划中进行的第二阶段的临床临床试验奠定基础。