Cytrochrome P45 2S1 gene regulation in human lung epithelial cells

人肺上皮细胞中细胞色素P45 2S1基因的调控

• 批准号: 7480235
• 负责人: AARON M ROWLAND
• 金额: $ 4.96万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-03 至 2009-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480235
• 关键词: A549; Agonist; Alveolar; Antibodies; Baculoviruses; Binding; Biological Assay; Caspase-1; Cells; Chemicals; Collaborations; Complex; Cultured Cells; Cytochrome P450; DNA-Binding Proteins; Disease; Electrophoretic Mobility Shift Assay; Elements; Enzymes; Epithelial Cells; Etiology; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Goals; Human; In Vitro; Indium; Length; Liver; Lung; Lung diseases; Mediating; Metabolic; Metabolism; Methods; Molecular Profiling; Monitor; Morbidity - disease rate; Mutate; Nuclear; Nucleotides; Oligonucleotides; Parents; Physiological; Polymerase Chain Reaction; Promoter Regions; Protein Overexpression; Proteins; Rate; Regulation; Reporter; Reporter Genes; Repression; Research; Retinoic Acid Receptor; Role; Site; Site-Directed Mutagenesis; Structure of parenchyma of lung; Time; Tissues; Toxic effect; Transcriptional Regulation; Tretinoin; Universities; Vitamin A; cell type; gene induction; human tissue; insight; liquid chromatography mass spectrometry; mortality; promoter; receptor; receptor binding; response; selective expression; transcription factor

DESCRIPTION (provided by applicant): Humans are exposed to a large variety of pneumotoxic or carcinogenic chemicals that exert their toxicities after bioactivation of the parent compound by cytochrome P450 enzymes. Additionally, metabolism by P450s is critical for maintaining the proper physiological levels of endogenous substrates. The selective response elicited in lung tissue by the presence of exogenous or endogenous compounds is primarily related to the selective expression and regulation of P450 genes in bronchiolar or alveolar epithelial cells, without concomitant expression in liver or other tissues. The hypothesis of this research is that the selective expression of the cvtochrome P450 2S1 (CYP2S1) gene in human lung epithelial cells is driven by unique, previously uncharacterized transcription factors; these factors act in concert to regulate its expression: and that regulated expression of CYP2S1 is an important mechanism for retinoic acid metabolism in lung epithelial cells. The major goal of this research is to precisely determine the factors that regulate CYP2S1 gene expression in lung cells and establish a role for CYP2S1 regulation of retinoic acid metabolism in lung epithelial cells. This goal will be realized through the following objectives: 1) identify unique promoter elements of the lung-selective P450 2S1 gene that defines functional transcriptional control by frans-acting nuclear factors from human lung tissues and cells that bind these core elements; 2) identify promoter elements and frans-acting nuclear factors involved in retinoic-acid mediated CYP2S1 gene induction; and to explore the contribution of CYP2S1 gene induction in the regulation of retinoic acid and its metabolites within the lung. Relevance: Lung diseases cause significant morbidity and mortality, and specific metabolic enzymes (P450s) contribute to the etiology of many of these diseases. These studies will provide vital, unique insight concerning the specific mechanisms that control expression of a recently identified P450 gene in lung cells and may provide significant insight into the tissue-selective metabolism and regulation of Vitamin A.

描述（由申请人提供）：人类暴露于多种肺毒性或致癌化学物质，这些化学物质在细胞色素 P450 酶对母体化合物进行生物激活后发挥其毒性。此外，P450 的代谢对于维持内源性底物的适当生理水平至关重要。外源性或内源性化合物的存在在肺组织中引起的选择性反应主要与细支气管或肺泡上皮细胞中 P450 基因的选择性表达和调节有关，而在肝脏或其他组织中不伴随表达。这项研究的假设是，人肺上皮细胞中细胞色素 P450 2S1 (CYP2S1) 基因的选择性表达是由独特的、以前未表征的转录因子驱动的。这些因素协同作用来调节其表达：并且CYP2S1的表达调节是肺上皮细胞中视黄酸代谢的重要机制。本研究的主要目标是精确确定肺细胞中CYP2S1基因表达的调节因素，并确定CYP2S1在肺上皮细胞中视黄酸代谢的调节作用。这一目标将通过以下目标实现：1) 鉴定肺选择性 P450 2S1 基因的独特启动子元件，该基因定义了来自人肺组织和细胞的反式作用核因子与这些核心元件结合的功能性转录控制； 2)鉴定参与视黄酸介导的CYP2S1基因诱导的启动子元件和反式作用核因子；并探讨CYP2S1基因诱导在肺内视黄酸及其代谢物调节中的作用。相关性：肺部疾病导致显着的发病率和死亡率，而特定的代谢酶 (P450) 是许多这些疾病的病因。这些研究将为控制肺细胞中最近发现的 P450 基因表达的具体机制提供重要、独特的见解，并可能为维生素 A 的组织选择性代谢和调节提供重要的见解。