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: 8167440
• 负责人: Jennifer R Chase
• 金额: $ 7.53万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167440
• 关键词: Acetaldehyde; Affect; Alcohol abuse; Alcohol dehydrogenase; Alcoholism; Alcohols; Aldehydes; All-Trans-Retinol; Cells; Computer Retrieval of Information on Scientific Projects Database; Computer Simulation; Disease; Enzymes; Ethanol; Fetal Alcohol Syndrome; Funding; Grant; Hela Cells; Hepatic Stellate Cell; Hepatocyte; Homeostasis; Human; In Vitro; Institution; Kinetics; Liver Cirrhosis; Liver diseases; Malignant Neoplasms; Measures; Metabolic Pathway; Metabolism; Modeling; NADH; Pathway interactions; Protein Isoforms; Research; Research Personnel; Resources; Retinoids; Signal Transduction; Signaling Molecule; Source; Systems Biology; Tretinoin; United States National Institutes of Health; alcohol effect; design; in vivo; liver function; oxidation; role model

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 酗酒和酒精滥用是公众关注的重大问题，会导致胎儿酒精综合症、肝硬化和呼吸消化道癌症。据推测，酗酒导致这些疾病的机制之一是破坏有效的细胞信号分子视黄酸的稳态。目前还没有视黄醇相关途径及其在肝脏疾病中的失调的综合模型。因此，关于视黄醇到视黄酸途径中哪些酶在体内重要、哪些酶受乙醇或其代谢物影响以及影响程度如何，存在相当多的争论。我们假设乙醇诱导的 NADH 和乙醛 (Ach) 增加通过抑制乙醛和乙醇脱氢酶而显着抑制人肝细胞中视黄酸的合成。在特定目标 1 中，我们将通过计算模拟乙醇诱导的 NADH 和 Ach 变化对 ADH 异构体氧化视黄醇的影响。在特定目标 2 中，我们将在 Ach 和 NADH 水平存在的情况下测量 recADH1 和 7 亚型的体外视黄醇氧化动力学，以匹配计算参数。在具体目标 3 中，我们将评估 NADH 和 Ach 升高对 HeLa-ADH1B 和 HeLa-ADH1B-ALDH2 细胞视黄醇氧化的影响。最后，在具体目标 4 中，我们将设计人类肝星状细胞中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开发一个更好的模型，来研究细胞信号传导模型视黄酸在正常肝功能中的作用及其对酒精相关疾病的破坏。