Small molecule screen to enhance epithelial repair

小分子筛选增强上皮修复

• 批准号: 8190379
• 负责人: Barry R Stripp
• 金额: $ 23.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190379
• 关键词: Adult; Agonist; Area; Asthma; Behavior; Biological Assay; Biopsy; Bronchiolitis Obliterans; Cell Communication; Cells; Chemicals; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical; Clonal Expansion; Coculture Techniques; Data; Defect; Deterioration; Development; Disease; Distal; Dose; Environment; Epithelial; Epithelial Cells; FDA approved; Fibroblasts; Fluorescence; Funding; Goals; Growth; Homeostasis; Human; In Vitro; Individual; Injury; Intervention; Lead; Libraries; Lung; Maintenance; Measures; Modeling; Mus; Natural regeneration; Patients; Pharmaceutical Preparations; Population; Process; Property; Pulmonary Fibrosis; Relative (related person); Reporter; Respiratory physiology; Screening procedure; Signal Pathway; Signal Transduction; Stem cells; Stromal Cells; Structure; Syndrome; System; Therapeutic Intervention; Tissues; Transgenic Mice; Translations; Work; Wound Healing; candidate identification; cell behavior; cell growth; cell type; drug candidate; improved; in vitro Assay; in vitro Model; in vivo; insight; interstitial; novel; pre-clinical; red fluorescent protein; repaired; response; self-renewal; small molecule; tissue processing; tool

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.

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，这些特征导致组织稳态丧失和肺功能恶化。越来越多的人支持这样的观点，即上皮细胞和成纤维细胞之间的信号变化是驱动缺陷性上皮维持/修复和组织重塑的关键因素。本提案的目标是确定上皮细胞-成纤维细胞相互作用的小分子调节剂，其具有促进上皮细胞再生的潜力。我们已经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。在该体外模型中，上皮祖细胞的扩增依赖于基质细胞相互作用，其重现了完整肺中的细胞-细胞相互作用。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（目的1）。将进行二次筛选以确定所鉴定的化合物是否对小鼠气道的三种不同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，并将确定有潜力增强上皮修复和恢复慢性肺病患者肺功能的候选药物。 公共卫生关系：慢性肺疾病具有上皮修复缺陷和纤维增生的共同特征，其导致组织稳态的丧失和肺功能的进一步恶化。该提案旨在确定可以减轻慢性肺部疾病患者组织重塑的新药。