SYSTEMS BIOLOGY MODELING OF ETHANOL?S EFFECTS ON HUMAN RETINOID METABOLISM

乙醇对人类视黄醇代谢影响的系统生物学模型

• 批准号: 8359686
• 负责人: Jennifer R Chase
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359686
• 关键词: Acetaldehyde; Affect; Alcohol abuse; Alcohol dehydrogenase; Alcoholism; Alcohols; All-Trans-Retinol; Cells; Computer Simulation; Disease; Enzymes; Ethanol; Fetal Alcohol Syndrome; Funding; Grant; Hela Cells; Hepatic Stellate Cell; Hepatocyte; Homeostasis; Human; Idaho; In Vitro; Kinetics; Liver Cirrhosis; Liver diseases; Malignant Neoplasms; Measures; Metabolic Pathway; Metabolism; Modeling; NADH; National Center for Research Resources; Pathway interactions; Principal Investigator; Protein Isoforms; Research; Research Infrastructure; Resources; Retinoids; Signal Transduction; Signaling Molecule; Source; Systems Biology; Tretinoin; United States National Institutes of Health; alcohol effect; aldehyde dehydrogenases; cost; design; in vivo; liver function; oxidation; programs; role model

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Alcoholism and alcohol abuse are significant public concerns, leading to fetal alcohol syndrome, liver cirrhosis and aerodigestive cancers. It is hypothesized that one mechanism by which alcoholism leads to these diseases is via disruption of homeostasis of the potent cell-signaling molecule, retinoic acid. Currently there is no comprehensive model of retinol-related pathways, nor their dysregulation in liver disease. As a consequence there is considerable debate about which enzymes on the pathway of retinol to retinoic acid are significant in vivo and which are affected by ethanol or its metabolites, and to what degree. We hypothesize that the ethanol-induced increases in NADH and acetaldehyde (Ach) significantly inhibit retinoic acid synthesis in human liver cells by inhibition of aldehyde and alcohol dehydrogenases. In specific Aim 1 we will computationally model the effect of ethanol-induced changes in NADH and Ach on retinol oxidation by ADH isoforms. In Specific Aim 2 we will measure in vitro retinol oxidation kinetics of recADH1 and 7 isoforms, in the presence of Ach and NADH levels to match the computational parameters. In Specific Aim 3 we will assess the impact of elevated NADH and Ach on retinol oxidation by HeLa-ADH1B, and HeLa-ADH1B-ALDH2 cells. Finally, in Specific Aim 4 we will design a computational model of the retinol metabolic pathways present in human hepatic stellate cells. Results from these studies will enable us to develop a better model for the role of the cell-signaling model retinoic acid in normal liver function and its disruption in alcohol-related disease.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 酒精中毒和酗酒是公众的重大关注，导致胎儿酒精综合征，肝硬化和机动癌症。假设酒精中毒导致这些疾病的一种机制是通过破坏有效细胞信号分子维甲酸的稳态。目前，没有视黄醇相关途径的全面模型，也没有其在肝病中的失调。因此，关于视黄醇到视黄酸的途径的酶在体内具有重要意义，并且受乙醇或其代谢产物的影响，以及在何种程度上存在很大的争议。我们假设乙醇诱导的NADH和乙醛（ACH）通过抑制醛和酒精脱氢酶而显着抑制人肝细胞中的视黄酸合成。在特定目标1中，我们将在计算上对乙醇诱导的NADH和ACH的变化对ADH同工型的视黄醇氧化的影响进行模拟。在特定目标2中，我们将在存在ACH和NADH水平的情况下测量RecadH1和7同工型的体外视黄醇氧化动力学，以匹配计算参数。在特定目标3中，我们将评估升高的NADH和ACH对HELA-ADH1B和HELA-ADH1B-ALDH2细胞的视黄醇氧化的影响。最后，在特定目标4中，我们将设计人类肝星细胞中存在的视黄醇代谢途径的计算模型。这些研究的结果将使我们能够为细胞信号模型视黄酸在正常肝功能中的作用及其在酒精相关疾病中的破坏而开发更好的模型。