Function and Regulation of Human Cytochrome P4502S1

人细胞色素P4502S1的功能和调控

• 批准号: 7811735
• 负责人: OLIVER nmn HANKINSON
• 金额: $ 43.51万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7811735
• 关键词: Acute; Address; Affect; Air Pollutants; Asthma; Chemicals; Chronic Phase; Complex; Cytochrome P450; Cytochromes; Diesel Exhaust; Disease; Eicosanoid Degradation; Eicosanoids; Environmental Risk Factor; Enzymes; Frequencies; Funding; Future; Grant; Human; Human Cell Line; Hypoxia; Hypoxia Inducible Factor; Individual; Indole-3-Carbinol; Integration Host Factors; Irrigation; Knock-out; Knockout Mice; Leukotrienes; Ligands; Lipoxins; Liquid substance; Lung; Mediating; Metabolism; Microsomes; Modeling; Molecular Target; Mus; Pharmaceutical Preparations; Play; Population; Process; Protocols documentation; Public Health; Recovery; Regulation; Role; Serum; Severities; Symptoms; Testing; Therapeutic Agents; Tissues; United States National Institutes of Health; Vegetables; Wild Type Mouse; Work; aryl hydrocarbons; asthma prevention; eicosanoid metabolism; enzyme activity; inhibitor/antagonist; insight; mimetics; mouse model; novel; novel therapeutics; parent grant; particle; protective effect; public health relevance; response

DESCRIPTION (provided by applicant): This application represents a Competitive Revision to grant R01ES015384, in response to the Notice Number (NOT-OD-09-058) and Notice Title: NIH Announces the Availability of Recovery Act funds for Competitive Revision Applications. In the parent grant, we are analyzing the function and enzymatic activity of the enzyme, cytochrome P450 2S1 (CYP2S1). In this revision, "CYP2S1 and Asthma", we will now extend these studies to investigate the role of CYP2S1 in the initiation and progression of asthma. Several of our (unpublished) observations suggest that this enzyme plays a role in this disease, and in particular, may function as a counter- regulatory mechanism to diminish the severity of individual asthmatic episodes. These observations include the following. (a) Cyp2s1 is highly expressed in mouse (and human) lung. (b) Hypoxia upregulates Cyp2s1 expression in mouse and human cell lines and in mouse lung in a process mediated by Hypoxia Inducible Factor (HIF). (c) HIF is required for the asthma-like response in a mouse model of asthma. (d) Cyp2s1 is upregulated in mouse lung during the asthma-like response. (e) Cyp2s1 is very active in the degradation of eicosanoids, many of which are known to be intimately involved in the initiation and progression of asthma. Specific Aim 1 will test our hypothesis that Cyp2s1 activity diminishes the asthmatic response. To this end, a newly developed knockout mouse for Cyp2s1 will be utilized to ascertain whether loss of Cyp2s1 activity enhances the manifestations of asthma-like symptoms in both the acute and chronic phases. Specific Aim 2 will test our hypothesis that the profile of eicosanoids differs between Cyp2s1 knockout and wild-type mice during the asthma-like response, thus providing a potential explanation for the enhanced asthma-like response in the former. To this end, (a) the metabolism of relevant eicosanoids by purified mouse Cyp2s1 and by microsomes from both types of the above mice treated or untreated with the asthma-inducing protocol, will be examined, and (b) the profiles of eicosanoids in lungs, bronchiolar lavage fluid (BAL) and sera from these mice will be determined. Specific Aim 2 will thereby identify eicosanoids whose concentrations in mouse tissues correlate with the severity of the asthma-like response, and also determine whether these eicosanoids are substrates of Cyp2s1, thus identifying the particular eicosanoid(s) that are likely responsible for mediating the protective effect of Cyp2s1 towards the asthma-like response. Our studies will potentially point to a novel target for asthma therapy, namely CYP2S1. Our previous studies suggest that certain natural compounds found in vegetables can upregulate Cyp2s1. These compounds therefore may represent potential novel therapeutics for asthma. PUBLIC HEALTH RELEVANCE: These studies will provide mechanistic insight into an important environmental disease - asthma. Furthermore, they promise to identify the enzyme CYP2S1 as a novel molecular target for agents for the treatment, amelioration or prevention of asthma. Such agents could include certain natural chemicals that impact the activity of CYP2S1, which are found in vegetables.

描述（申请人提供）：本申请代表对授予R01ES015384的竞争性修订，以响应通知号（NOT-OD-09-058）和通知标题：NIH宣布了竞争性修订申请的恢复ACT资金的可用性。在父授予中，我们正在分析酶，细胞色素P450 2S1（CYP2S1）的功能和酶活性。在此修订版中，“ CYP2S1和哮喘”，我们现在将扩展这些研究，以研究CYP2S1在哮喘的启动和进展中的作用。我们的一些（未发表的）观察结果表明，该酶在该疾病中起作用，尤其是可以作为降低个体哮喘发作严重程度的反调节机制。这些观察结果包括以下内容。 （a）CYP2S1在小鼠（和人）肺中高度表达。 （b）在由缺氧诱导因子（HIF）介导的过程中，缺氧上调小鼠和人类细胞系和小鼠肺中的CYP2S1表达。 （c）在哮喘小鼠模型中，需要HIF才需要HIF。 （d）在类似哮喘的反应期间，小鼠肺中的CYP2S1上调。 （e）CYP2S1在类花生酸的降解中非常活跃，其中许多众所周知，其中许多与哮喘的起始和进展密切相关。具体目标1将检验我们的假设，即CYP2S1活性会减少哮喘反应。为此，将利用一种新开发的用于CYP2S1的淘汰小鼠来确定CYP2S1活性的丧失是否会增强急性和慢性相中哮喘样症状的表现。具体目标2将检验我们的假设，即类似类似哮喘的反应期间，类花生酸的特征在CYP2S1敲除和野生型小鼠之间有所不同，从而为前者增强的类似哮喘的反应提供了潜在的解释。为此，（a）将检查通过纯化的鼠标CYP2S1和来自两种类型的上述小鼠的微粒体的相关类花生酸酯的代谢，将检查或未通过哮喘诱导方案进行处理，（b）（b）肺，肺泡，be beagage auvage fluiid（BAL）和SERA的eicosanoids的特征（b）来自这些MECEA的eicosanoids seraa and Sera sera sera and Sera sera M.Sera和Sera Mestem sera M.特定目标2因此，将确定其在小鼠组织中的浓度与哮喘样反应的严重程度相关的类固醇，还确定这些类固醇是否是CYP2S1的底物，从而确定了可能介导CYP2S1对ASTHMA样响应的保护作用。我们的研究可能会指出哮喘治疗的新靶标，即CYP2S1。我们以前的研究表明，在蔬菜中发现的某些天然化合物可以上调CYP2S1。因此，这些化合物可能代表哮喘的潜在新型治疗剂。 公共卫生相关性：这些研究将为重要的环境疾病 - 哮喘提供机械洞察力。此外，他们承诺将酶CYP2S1识别为治疗，改善或预防哮喘的新型分子靶标。这样的药物可能包括某些影响CYP2S1活性的天然化学物质，这些化学物质在蔬菜中发现。