Impact of Alcohol on HIV Protease Inhibitor-induced ER Stress and Lipotoxicity

酒精对 HIV 蛋白酶抑制剂诱导的内质网应激和脂毒性的影响

• 批准号: 8331653
• 负责人: HUIPING Rose ZHOU
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331653
• 关键词: AIDS/HIV problem; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Apoptosis; Apoptotic; Attenuated; CCAAT-Enhancer-Binding Proteins; Calcium; Caring; Cessation of life; Clinic; Clinical; Cytosol; Development; Endoplasmic Reticulum; Epidemic; Fatty Liver; Functional disorder; Future; General Population; Goals; HIV; HIV Infections; HIV Protease Inhibitors; Health; Hepatic; Hepatocyte; Hepatotoxicity; Highly Active Antiretroviral Therapy; Homeostasis; Homologous Protein; Incidence; Inflammation; Injury; Knock-out; Life; Link; Lipids; Liver; Liver diseases; Mediator of activation protein; Medical; Metabolic syndrome; Mitochondria; Molecular; Mus; Nutrient; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Population; Prevalence; Process; Proteins; Provider; Quality of life; Reporting; Research; Risk Factors; Role; Severities; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic; United States; Veterans; Wit; alcohol misuse; base; cell type; effective therapy; endoplasmic reticulum stress; human disease; improved; macrophage; novel; response

DESCRIPTION (provided by applicant): The hepatic lipotoxicity specifically associated with HIV protease inhibitors (PIs), the core component of highly active anti-retroviral therapy (HAART), has become a major concern in the clinic, especially in patients who consume alcohol. Alcohol abuse, which alone also produces liver toxicity, is one of the most important co-morbid risk factors for liver injury in HIV patient under current therapy. Despite the prevalence of this problem and its serious impact on the quality of life and continued therapy in HIV patients, the mechanism by which alcohol exacerbates HIV PI-induced hepatic lipotoxicity has not been identified. The goal of this proposal is to examine the potential impact of alcohol use/abuse on HIV PI- induced hepatic lipotoxicity and further elucidate the underlying cellular/molecular mechanisms. The central hypothesis of this study is that alcohol and HIV PIs additively induce hepatic lipotoxicity by activating the ER stress, subsequently disrupting lipid homeostasis and inducing apoptosis in hepatocytes. In this study, we will (1) determine the impact of alcohol on HIV PI-induced activation of ER stress, (2) determine the role of ER stress in alcohol and HIV PI-induced hepatic lipotoxicity and (3) identify the mechanism by which alcohol promotes HIV PI-induced ER stress and hepatic lipotoxicity. The long-term goal of this research is to understand the molecular/cellular mechanisms by which alcohol and HAART induce hepatic lipotoxicity. The burden of liver injury in HIV patients is expected to increase as the number of patients living wit HIV continues to rise. Understanding the mechanism by which alcohol and HIV PIs induce hepatotoxicity is of great clinical importance. Completion of these objectives will help identify new cellular mechanisms of alcohol and HIV PI-induced hepatic lipotoxicity, thereby enhancing our understanding of the mechanisms of HAART-associated liver diseases and providing novel information for the future development of new preventative and therapeutic strategies.

描述（由申请人提供）：