PHYSIOLOGICAL REGULATION OF PULMONARY GENE EXPRESSION

肺基因表达的生理调节

• 批准号: 6330175
• 负责人: Francesco John DeMayo
• 金额: $ 23.54万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-08 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6330175
• 关键词: cell line; cytoprotection; gene expression; genetic promoter element; genetically modified animals; hyperoxia; interferon gamma; laboratory mouse; lung injury; respiratory epithelium; secretory protein; transcription factor

A significant function of the pulmonary epithelium is to protect the lung from damage while maintaining a homeostatic balance between these protective processes and the processes allowing for the exchange of gasses. One of the pulmonary epithelial cell types involved in the maintenance of this homeostatic balance is the non-ciliated secretory cell of the bronchiolar epithelium, the Clara cell. The major secretory product of the Clara cell is a homodimeric 16 kDa protein, Clara cell secretory protein, CCSP. Biochemical analysis and gene ablation studies have demonstrated that this protein protects the lungs in cases of environmental insult, such as a hyperoxic challenge. Glucocorticoids, cytokines and oxygen regulate the expression of this gene. Initial analysis of the elements regulating the expression of this gene has defined transcription factors which govern the pulmonary specific expression of this gene. It is the goal of this proposal to investigate the means by which cytokines and oxygen affect the interactions of these transcription factors in the regulation of the expression of the CCSP gene. This will be accomplished by achieving the following specific aims: The identification of elements in the distal promoter of the CCSP gene regulating Clara cell specific expression. Identification of the elements in the CCSP promoter which are responsible for regulation by Interferon-gamma (IFN-gamma). Investigation of the molecular mechanism governing the repressive effect of hyperoxia on CCSP expression. Examine the physiological effects of hyperoxia on a mouse whose CCSP gene promoter elements have has been made irresponsive to oxygen. The definition of the interactions of these regulatory elements will allow the identification of the molecular mechanisms governing the physiological regulation of this gene. An understanding of these processes will allow the development of approaches to protect the lung against hyperoxic and inflammatory insult. Therefore, the goal of this proposal is to define the molecular mechanisms involved in the physiological expression of the CCSP gene and examine the physiological consequences of disrupting these molecular processes.

肺上皮的一个重要功能是保护 肺免受损伤，同时保持这些之间的稳态平衡 保护过程和允许交换的过程 气体。 参与肺上皮细胞类型之一 维持这种稳态平衡的是非纤毛分泌 细支气管上皮细胞，克拉拉细胞。 主要秘书 Clara 细胞的产物是同源二聚体 16 kDa 蛋白，Clara 细胞 分泌蛋白，CCSP。生化分析和基因消融研究 已经证明这种蛋白质在以下情况下可以保护肺部 环境损害，例如高氧挑战。 糖皮质激素， 细胞因子和氧调节该基因的表达。最初的 对该基因表达调控元件的分析 确定的转录因子控制肺部特异性 该基因的表达。 本提案的目的是调查 细胞因子和氧气影响这些相互作用的方式 CCSP表达调控中的转录因子 基因。 这将通过实现以下具体目标来实现 目的：CCSP 远端启动子中元件的鉴定 调控Clara细胞特异性表达的基因。 鉴定 CCSP 启动子中的元件负责调节 干扰素-γ（IFN-γ）。 抑制作用的分子机制研究 高氧对 CCSP 表达的影响。 检查生理效应 CCSP 基因启动子元件已被置于高氧状态的小鼠 对氧气无反应。 相互作用的定义 这些调控元件将允许识别分子 控制该基因的生理调节的机制。 一个 了解这些过程将有助于开发 保护肺部免受高氧和炎症的方法 侮辱。因此，该提案的目标是定义分子 CCSP基因生理表达的机制 检查破坏这些分子的生理后果 流程。