Regulation of PTEN in chronic alcohol mediated liver disease

PTEN 在慢性酒精介导的肝病中的调节

• 批准号: 7910036
• 负责人: Colin Shearn
• 金额: $ 5.58万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7910036
• 关键词: Address; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Aldehydes; Chronic; Cirrhosis; Cysteine; Diagnosis; Ethanol; Ethanol toxicity; Fatty Liver; Immunohistochemistry; Lipid Binding; Lipids; Liquid substance; Liver; Liver diseases; Mass Spectrum Analysis; Mediating; Modeling; Modification; Morbidity - disease rate; Mus; Oxidative Stress; PTEN gene; Pathway interactions; Phosphoric Monoester Hydrolases; Proteins; Publications; Regulation; Reporting; Research Proposals; Role; Signal Pathway; Signal Transduction; Site; Survival Rate; Symptoms; Time; United States; Western Blotting; Work; adduct; alcohol exposure; insight; mRNA Expression; membrane activity; mortality; public health relevance; research study; statistics

DESCRIPTION (provided by applicant): The objective of this proposal is to determine the involvement of the lipid phosphatase PTEN in the formation of steatosis and liver damage during alcoholic liver disease (ALD). Although there are publications concerning the role of PTEN in ALD, these reports are using a static time point in a fluid model and do not address the possibility of both PTEN inactivation via aldehyde modification and changes in PTEN regulation/expression over a period of alcohol exposure. Our working hypothesis states the reactive aldehyde 4-HNE, produced in the liver of chronic ethanol treated mice covalently adducts PTEN thereby reducing enzymatic activity leading to disregulation in PTEN downstream signaling. 4-HNE has already been implicated in the inactivation of proteins during chronic ethanol exposure in the liver. It is also hypothesized that increased PTEN expression leads to changes in downstream pathways ultimately leading to increased steatosis seen in ALD. In order to fulfill the objectives of this research proposal, experiments will be performed using mass spectrometry to identify the sites of 4-HNE modification on PTEN, the ability of these adducts to inhibit enzymatic activity, membrane association and Trx1 association. In addition, using western blotting, immunohistochemistry and mRNA expression, the effects of variable PTEN expression on downstream signaling pathways will be examined following 9-weeks of chronic ethanol exposure. PUBLIC HEALTH RELEVANCE: In the United States today, alcohol induced liver disease is a major cause of morbidity and mortality. Current statistics indicate that among chronic alcohol users, 15% will eventually be diagnosed with alcoholic liver disease. These symptoms include steatosis, alcoholic hepatitis and cirrhosis. The 5 and 10 year survival rates for alcohol induced cirrhosis are 23% and 7% respectively. Completion of the proposed experiments will provide greater insight into the mechanisms of chronic alcohol toxicity especially with respect to steatosis and damage caused by increased oxidative stress and altered PTEN signaling.

描述（由申请人提供）：本提案的目的是确定脂质磷酸酶 PTEN 在酒精性肝病 (ALD) 期间脂肪变性和肝损伤形成中的参与。尽管有一些出版物涉及 PTEN 在 ALD 中的作用，但这些报告在流体模型中使用静态时间点，并没有解决通过醛修饰导致 PTEN 失活以及在酒精暴露一段时间内 PTEN 调节/表达发生变化的可能性。我们的工作假设指出，长期乙醇处理的小鼠肝脏中产生的反应性醛 4-HNE 与 PTEN 共价加合物，从而降低酶活性，导致 PTEN 下游信号传导失调。 4-HNE 已被证实与肝脏长期接触乙醇期间蛋白质失活有关。还假设 PTEN 表达增加会导致下游通路发生变化，最终导致 ALD 中脂肪变性增加。为了实现本研究计划的目标，将使用质谱法进行实验来鉴定 PTEN 上 4-HNE 修饰的位点、这些加合物抑制酶活性、膜关联和 Trx1 关联的能力。此外，将使用蛋白质印迹、免疫组织化学和 mRNA 表达，在慢性乙醇暴露 9 周后检查可变 PTEN 表达对下游信号通路的影响。 公共卫生相关性：在当今的美国，酒精引起的肝病是发病和死亡的主要原因。目前的统计数据表明，在长期饮酒者中，15%最终会被诊断为酒精性肝病。这些症状包括脂肪变性、酒精性肝炎和肝硬化。酒精引起的肝硬化的 5 年和 10 年生存率分别为 23% 和 7%。完成所提出的实验将更深入地了解慢性酒精毒性的机制，特别是在脂肪变性和氧化应激增加和 PTEN 信号改变引起的损伤方面。