Targeting epithelial cells to treat pulmonary fibrosis

描述：这项翻译计划项目赠款旨在开发治疗特发性肺纤维化(IPF)的新的有效疗法。这笔赠款完全集中在开发新药上，这些新药专门针对肺泡上皮细胞中的已知通路，这些通路对肺纤维化的发展至关重要。这笔赠款还将使用一种新的、基于机制的方法来从人类细胞和组织中识别信息丰富的生物标记物，这应该会为我们在随后的IPF患者早期临床试验中开发的每种药物的有效性提供早期指标。这项拨款的基本原理是，肺间质纤维化是持续的上皮应激和细胞凋亡的结果，这导致肺泡上皮细胞上整合素αnuβ激活细胞外潜伏的转化生长因子β，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转化生长因子β信号。该提案包括3个项目，每个项目将利用多个小鼠肺纤维化模型来评估现有药物的有效性，这些药物针对由未折叠蛋白反应、整合素介导的TGFbeta激活和TGFbeta信号诱导的上皮细胞凋亡，并开发具有更高效力和降低全身毒性的新药物。通过平行分析这些药物对人肺泡上皮细胞和人肺碎片的影响，这些项目将进一步降低小鼠的研究结果对人类的适用性。每个项目还将利用来自IPF患者和健康对照组的血液、BAL细胞和液体的系列样本来表征假定具有生物信息的生物标记物的用途和重复性。这些项目将由一个人类肺细胞和组织核心、一个纵向队列核心、一个医学化学核心和一个集中管理核心提供支持。通过对最有希望的候选药物进行扩展的临床前分析，确定它们在人类肺部的有效性，并开发可以在血液、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读数，所做的工作应该为该计划计划的第二阶段中最有希望的候选药物的临床试验奠定基础。

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.