Small molecule screen to enhance epithelial repair

描述（由申请人提供）：慢性肺部疾病具有上皮修复缺陷和纤维增生的共同特征，导致组织稳态丧失和肺功能恶化。越来越多的研究支持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细胞维持/修复和组织重塑的关键因素。本研究的目的是确定上皮-成纤维细胞相互作用的小分子调节因子，这些调节因子有促进上皮再生的潜力。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，上皮祖细胞的扩增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细胞间的相互作用。该体外试验将用于筛选FDA批准的化合物库，以确定其调节上皮祖细胞生长的能力（Aim 1）。将进行二次筛选，以确定所鉴定的化合物是否对三种不同的小鼠气道祖细胞类型具有广谱或选择性活性（目的2）。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，并将确定有可能增强慢性肺病患者上皮修复和恢复肺功能的候选药物。

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.