Hepatic CYP enzymes and host-pathogen interactions

肝脏 CYP 酶和宿主-病原体相互作用

基本信息

批准号：
8431436
负责人：
Edward Thomas Morgan
金额：
$ 35.68万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8431436
关键词：
Address Adverse effects Affect Alkane 1-monooxygenase Bacteria Bacterial Infections Biochemical Blood Circulation CYP4A11 gene Complement Conditioned Culture Media Cytochrome P450 Disease Down-Regulation Endotoxins Enzymes Escherichia coli Escherichia coli Infections Exhibits Fatty Acids Flavins Food Poisoning Funding Gene Deletion Gene Expression Genetic Hepatic Hepatocyte Human Immune response Impairment Individual Infection Inflammation Inflammatory Invaded Kidney Libraries Liver Measurement Mixed Function Oxygenases Modeling Mus Oxidative Stress Pathology Pharmaceutical Preparations Play Proteomics Publishing Regulation Role Serum Severities Signal Pathway Signal Transduction Stimulus Therapeutic Effect Tissues Transgenic Mice blood pressure regulation cytokine drug clearance eicosanoid metabolism enteropathogenic Escherichia coli fatty acid metabolism gastrointestinal in vivo lipid metabolism liver metabolism mutant novel oxidative damage pathogen public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Cytochrome P450 (P450) enzymes play crucial roles in the clearance of drugs from the circulation, and therefore changes in their activities can significantly influence the therapeutic and adverse effects of a drug on an individual. Infectious and inflammatory diseases cause the down-regulation of many P450s and other drug metabolizing enzymes in the liver, causing impairment of drug clearances. In mice infected with C. rodentium, a model of E. Coli food poisoning in humans, a number of P450 enzymes in the liver are moderately down-regulated. However, CYP4A enzymes are more profoundly affected, as is another drug metabolizing enzyme, i.e. flavin monooxygenase 3 (FMO3). Preliminary evidence suggests that one or more bacterially secreted factors regulate hepatic CYP4A expression in an endotoxin-independent manner. CYP4As have important roles in fatty acid metabolism, control of blood pressure and in oxidative stress. Therefore, it is important to understand how human CYP4A11 is regulated during infection, and to understand whether on not CYP4A regulation is a defensive or adaptive response of the host, or if the invading bacterium could be regulating CYP4As to its own advantage. To address these questions, the regulation of CYP4A11 will be studied in the livers and kidneys of CYP4A11 transgenic mice during C. rodentium infection. This will be complemented by studies in cultured human hepatocytes and in CYP4A11 transgenic mouse hepatocytes, on CYP4A11 regulation by inflammatory cytokines and bacterial products. Transcriptional and proteomic profiling will be used to assess the effects of infection on global gene expression in the liver and to elucidate signaling networks involved in CYP4A and FMO3 down-regulation by factors secreted by bacteria. To identify these factor(s) we will screen known mutants and, if necessary, an enteropathogenic E. coli transposon insertion library to identify mutants that fail to down-regulate these enzymes. This approach will be complemented by biochemical characterization and partial purification of the factor(s). To elucidate the role of CYP4A enzymes in the host response to C. rodentium infection, or as targets of the bacterium's strategy for propagation and survival, the effects will be studied of Cyp4A10-/- and Cyp4A14-/- gene deletion on the pathologies associated with C. rodentium infection.

描述（由申请人提供）：细胞色素P450（P450）酶在清除循环中的药物中起着至关重要的作用，因此其活动的变化可以显着影响药物对个体的治疗和不良影响。传染病和炎症性疾病导致肝脏中许多P450和其他药物代谢酶的下调，从而导致药物清除障碍。在感染啮齿动物梭菌的小鼠中，人类大肠杆菌食物中毒的模型，肝脏中的许多P450酶被中度下调。然而，CYP4A酶受到更深远的影响，另一种药物代谢酶也受到了影响，即黄素单加氧酶3（FMO3）。初步证据表明，一个或多个细菌分泌的因素以内毒素独立的方式调节肝CYP4A的表达。 CYP4A在脂肪酸代谢，控制血压和氧化应激中具有重要作用。因此，重要的是要了解在感染过程中如何调节人类CYP4A11，并了解不进行CYP4A调节是宿主的防御或适应性反应，或者入侵细菌是否可以对CYP4AS对自己的优势进行调节。为了解决这些问题，将在啮齿动物念珠菌感染期间在CYP4A11转基因小鼠的肝脏和肾脏中研究CYP4A11的调节。这将通过对培养的人肝细胞和CYP4A11转基因小鼠肝细胞的研究，对CYP4A11通过炎症细胞因子和细菌产物调节的研究。转录和蛋白质组学分析将用于评估感染对肝脏全球基因表达的影响，并通过细菌分泌的因素来阐明参与CYP4A和FMO3涉及的信号网络。为了识别这些因素，我们将筛选已知的突变体，并在必要时筛选出肠病大肠杆菌转座子插入文库，以识别无法下调这些酶的突变体。这种方法将通过生化特征和因子的部分纯化来补充。 To elucidate the role of CYP4A enzymes in the host response to C. rodentium infection, or as targets of the bacterium's strategy for propagation and survival, the effects will be studied of Cyp4A10-/- and Cyp4A14-/- gene deletion on the pathologies associated with C. rodentium infection.

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Selective modulation of hepatic cytochrome P450 and flavin monooxygenase 3 expression during citrobacter rodentium infection in severe combined immune-deficient mice.

严重联合免疫缺陷小鼠柠檬酸杆菌感染期间肝细胞色素 P450 和黄素单加氧酶 3 表达的选择性调节。

DOI：
10.1124/dmd.112.046557
发表时间：
2012
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
0
作者：
Nyagode,BeatriceA;Watkins,WilliamJ;Kinloch,RyanD;Morgan,EdwardT
通讯作者：
Morgan,EdwardT

Selective effects of a therapeutic protein targeting tumor necrosis factor-alpha on cytochrome P450 regulation during infectious colitis: Implications for disease-dependent drug-drug interactions.

DOI：
10.1002/prp2.27
发表时间：
2014-02-01
期刊：
PHARMACOLOGY RESEARCH & PERSPECTIVES
影响因子：
2.6
作者：
Nyagode, Beatrice A;Jahangardi, Roya;Merrell, Matthew D;Tansey, Malu G;Morgan, Edward T
通讯作者：
Morgan, Edward T

Altered inflammatory responses to Citrobacter rodentium infection, but not bacterial lipopolysaccharide, in mice lacking the Cyp4a10 or Cyp4a14 genes.

DOI：
10.1007/s10753-013-9809-6
发表时间：
2014-06
期刊：
INFLAMMATION
影响因子：
5.1
作者：
Nyagode, Beatrice A.;Williams, Ifor R.;Morgan, Edward T.
通讯作者：
Morgan, Edward T.

TLR4-dependent and -independent regulation of hepatic cytochrome P450 in mice with chemically induced inflammatory bowel disease.

DOI：
10.1016/j.bcp.2008.10.029
发表时间：
2009-02-01
期刊：
BIOCHEMICAL PHARMACOLOGY
影响因子：
5.8
作者：
Chaluvadi, Madhusudana R.;Nyagode, Beatrice A.;Kinloch, Ryan D.;Morgan, Edward T.
通讯作者：
Morgan, Edward T.