Targeting epithelial cells to treat pulmonary fibrosis

描述：该转化项目拨款旨在开发特发性肺纤维化（IPF）的新有效疗法。该基金完全专注于开发新药，专门针对肺泡上皮细胞中已知的对肺纤维化发展至关重要的途径。这笔拨款还将使用一种新颖的、基于机制的方法，从人类细胞和组织中识别信息丰富的生物标志物，这些生物标志物将为我们在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。该资助的基本原理是IPF是上皮细胞n向应激和凋亡的结果，这导致肺泡上皮细胞上的α - nu - β整合素激活细胞外潜伏tgf - β，这反过来至少诱导进行性纤维化

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.