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 Several of our (unpublished) observations suggest that this enzyme plays a role in this disease, and in particular, may function as a counter- regulatory mechanism to diminish the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（由申请人提供）：本申请代表授予R01ES015384的竞争性修订，响应通知编号（NOT-OD-09-058）和通知标题：NIH宣布竞争性修订申请的恢复法案资金的可用性。在亲本研究中，我们分析了细胞色素P450 2S1 （CYP2S1）酶的功能和酶活性。在这篇“CYP2S1与哮喘”的修订版中，我们将扩展这些研究，以研究CYP2S1在哮喘的发生和进展中的作用。我们的一些（未发表的）观察结果表明，这种酶在这种疾病中起作用，特别是，可能作为一种反调节机制，以减轻个体哮喘发作的严重程度。这些观察包括以下内容。(a) Cyp2s1在小鼠（和人）肺中高表达。(b)在缺氧诱导因子（Hypoxia Inducible Factor， HIF）介导的过程中，缺氧上调小鼠和人细胞系以及小鼠肺中Cyp2s1的表达。(c) HIF是哮喘小鼠模型中哮喘样反应所必需的。(d)哮喘样反应期间小鼠肺中Cyp2s1表达上调。(e) Cyp2s1在类二十烷的降解中非常活跃，其中许多已知与哮喘的发生和进展密切相关。特异性目标1将验证我们的假设，Cyp2s1活性减少哮喘反应。为此，将利用新开发的Cyp2s1敲除小鼠来确定Cyp2s1活性的丧失是否会增强急性和慢性哮喘样症状的表现。特异性目的2将验证我们的假设，即Cyp2s1敲除小鼠和野生型小鼠在哮喘样反应期间的类二十碳酸盐谱不同，从而为前者的哮喘样反应增强提供潜在的解释。为此，(a)将检查纯化小鼠Cyp2s1和上述两种小鼠的微粒体对相关类二十烷醇的代谢，这些小鼠的肺、细支气管灌洗液（BAL）和血清将测定这些小鼠的类二十烷醇的谱。因此，特异性Aim 2将确定其浓度在小鼠组织中与哮喘样反应的严重程度相关的类二十烷类化合物，并确定这些类二十烷类化合物是否是Cyp2s1的底物，从而确定可能负责介导Cyp2s1对哮喘样反应的保护作用的特定类二十烷类化合物。我们的研究将潜在地指向哮喘治疗的新靶点，即CYP2S1。我们之前的研究表明，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潜在的哮喘新疗法。