Small molecule screen to enhance epithelial repair

小分子筛选增强上皮修复

• 批准号: 8642708
• 负责人: Barry R Stripp
• 金额: $ 12.34万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8642708
• 关键词: Small; molecule; screen; enhance; epithelial

DESCRIPTION (provided by applicant): 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. 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 improve our ability regulate epithelial progenitor cells in health and disease, and to develop strategies to enhance epithelial regeneration. We have developed mouse lines and cell fractionation strategies that when coupled with a novel in vitro culture model allow us to quantify growth and differentiation of airway progenitor cells in small molecule screening assays. Expansion of epithelial progenitor cells is dependent upon stromal cell interactions that recapitulate cell-cell interactions in the intact lung that mediate normal tissue maintenance or remodeling. Goals of this application are to exploit this assay to screen a library of pharmacologically active small molecules to identify potentially novel therapeutics that can modulate epithelial progenitor cell growth and differentiation in vitro (Aim 1). Aim 2 will perform secondary assays to optimize lead compounds defined in Aim 1 and determine their ability to enhance epithelial growth in an in vitro model of idiopathic pulmonary fibrosis. Results from this application will identify chemical tools for manipulation of signaling pathways that regulate epithelial growth and differentiation. These studies will provide new information for the development of drugs capable of enhancing epithelial repair and restoration of lung function to 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，导致组织稳态丧失和肺功能进一步恶化。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。该提案的目标是提高我们在健康和疾病中调节上皮祖细胞的能力，并制定增强上皮再生的策略。我们已经开发了小鼠品系和细胞分级策略，当与新的体外培养模型相结合时，使我们能够在小分子筛选试验中量化气道祖细胞的生长和分化。上皮祖细胞的扩增依赖于基质细胞的相互作用，其再现了完整肺中介导正常组织维持或重塑的细胞-细胞相互作用。本申请的目的是利用该测定来筛选生物活性小分子的文库，以鉴定可以在体外调节上皮祖细胞生长和分化的潜在的新型治疗剂（目的1）。目的2将进行二次测定以优化目的1中定义的先导化合物，并确定它们在特发性肺纤维化的体外模型中增强上皮生长的能力。从这个应用程序的结果将确定化学工具的信号转导途径，调节上皮细胞的生长和分化的操纵。这些研究将为开发能够增强慢性肺病患者上皮修复和肺功能恢复的药物提供新的信息。