Small molecule screen to enhance epithelial repair

描述(申请人提供)：慢性肺部疾病具有上皮修复缺陷和纤维增殖的共同特征，这些特征导致组织动态平衡的丧失和肺功能的恶化。越来越多的人支持这样一种观点，即上皮细胞和成纤维细胞之间的信号变化是驱动有缺陷的上皮维护/修复和组织重建的关键因素。这项建议的目标是确定具有促进上皮再生潜力的上皮-成纤维细胞相互作用的小分子调节因子。我们开发了一种新的体外模型来研究肺上皮祖细胞在受控培养环境中的行为。在这个体外模型中，上皮祖细胞的扩张依赖于基质细胞的相互作用，这种相互作用概括了完整肺中的细胞-细胞相互作用。这一体外试验将用于筛选FDA批准的化合物库，以了解它们调控上皮祖细胞生长的能力(目标1)。将进行二次筛选，以确定已鉴定的化合物是否对三种不同类型的小鼠呼吸道祖细胞具有广谱或选择性活性(目标2)。研究结果将为上皮祖细胞和肺成纤维细胞之间的信号相互作用提供新的见解，并将确定具有促进上皮修复和恢复慢性肺病患者肺功能的潜在候选药物。 公共卫生相关性：慢性肺部疾病具有上皮修复缺陷和纤维增殖的共同特征，这些都会导致组织动态平衡的丧失和肺功能的进一步恶化。这项提案旨在确定可以减轻慢性肺病患者组织重塑的新药。

DESCRIPTION (provided by applicant): Chronic lung diseases share common features of epithelial repair defects and fibroproliferation that contribute to loss of tissue homeostasis and deterioration of lung function. There is growing support for the notion that signaling changes between epithelial cells and fibroblasts are key factors that drive defective epithelial maintenance/repair and tissue remodeling. Goals of this proposal are to identify small molecule regulators of epithelial-fibroblast interaction that have potential to promote epithelial regeneration. We have developed a novel in vitro model to investigate the behavior of lung epithelial progenitor cells in a controlled culture environment. Expansion of epithelial progenitor cells in this in vitro model is dependent upon stromal cell interactions that recapitulate cell-cell interactions in the intact lung. This in vitro assay will be used to screen a library of FDA approved compounds for their ability to regulate growth of epithelial progenitor cells (Aim 1). Secondary screening will be performed to determine whether the identified compounds have broad spectrum or selective activity towards three distinct progenitor cell types of mouse airways (Aim 2). Results will provide new insights into signaling interactions between epithelial progenitor cells and lung fibroblasts, and will identify candidate drugs with potential to enhance epithelial repair and restore lung function to patients with chronic lung disease. PUBLIC HEALTH RELEVANCE: Chronic lung diseases share the common feature of epithelial repair defects and fibroproliferation that contribute to loss of tissue homeostasis and further deterioration of lung function. This proposal seeks to identify new drugs that can mitigate tissue remodeling seen in patients with chronic lung disease.