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Primary role of Golgi stress in anti-HIV drug and alcohol abuse-induced hepatotoxicity

高尔基体应激在抗 HIV 药物和酒精滥用引起的肝毒性中的主要作用

基本信息

批准号：
9912135
负责人：
CHENG JI
金额：
$ 41.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912135
关键词：
AIDS/HIV problem ATF6 gene Acquired Immunodeficiency Syndrome Affect Alcohol abuse Alcohol consumption Alcohols Animal Model Anti-HIV Agents Anti-HIV Therapy Antioxidants Antiviral Agents Apoptosis Autophagocytosis Biological Models CASP2 gene CASP3 gene CRISPR/Cas technology Capsid Proteins Caring Caspase Cell Death Cells Chemicals Cirrhosis Coat Protein Complex I Coiled-Coil Domain Consensus Consumption Development Drug Targeting Drug abuse Endoplasmic Reticulum Ensure Exposure to Family Fatty Liver Fatty acid glycerol esters Functional disorder Gene Expression Genes Genetic Genetic Transcription Golgi Apparatus Golgi Targeting HIV HIV Infections HIV Protease Inhibitors HIV/HCV HepG2 Hepatitis B Virus Hepatitis C virus Hepatocyte Hepatotoxicity Homeostasis Hour Impairment In Vitro Inflammation Inflammatory Interleukin-1 Interleukin-6 Investigation Life Liver Liver Fibrosis Liver diseases Mediating Medicine Membrane Molecular Molecular Chaperones Monomeric GTP-Binding Proteins Morbidity - disease rate Mus Organelles Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Process Proteins Quality of life RIPK3 gene Risk Ritonavir Role Route SNAP receptor Signal Pathway Steatohepatitis Stress TFE3 gene TNF gene Time Vesicle Virus alcohol measurement biological adaptation to stress caspase 12 cellular targeting co-infection comorbidity compliance behavior endoplasmic reticulum stress improved in vivo Model inhibitor/antagonist lipid biosynthesis liver injury member mortality new therapeutic target novel overexpression problem drinker protective effect protein complex rab GTP-Binding Proteins side effect small hairpin RNA targeted treatment therapeutic target trafficking transcription factor

项目摘要

Anti-HIV or HIV-HCV/HBV co-infection drugs help people with HIV/AIDS live longer and healthier lives. However, the HIV medicines often cause side effects. Although most side effects from the HIV medicines are manageable, a few such as damages to the liver can be very serious and life threatening. To be worse, nearly half of the HIV infected patients abuse/consume alcohol or having a multiple drug-abuse problem, which not only impairs patients’ adherence to the anti-HIV therapy but also deteriorates antiviral-induced hepatotoxicity leading to greater morbidity and mortality. Hence molecular mechanisms and potential therapeutic targets underlying the hepatotoxicity are under intense investigations. Previous studies by us and others suggest that endoplasmic reticulum (ER) stress contributes to HIV protease inhibitors and/or alcohol abuse-induced hepatic cell death, steatohepatitis and cirrhosis in animal models and patients. However, therapies to ensure proper ER homeostasis such as applications of chemical chaperones, antioxidants, autophagy inducers, or selective enhancement of protective ER signaling pathways only yield partial effects in a variety of in vitro and in vivo model systems, which suggest that other more precise cellular targets are involved in the anti-HIV drugs and/or alcohol-induced hepatotoxicity. Our most recent studies reveal a strong effect of certain HIV protease inhibitors on the ER-Golgi trafficking and integrity of the Golgi apparatus, which occurs earlier than the ER stress response and results in increased cell death compared to the cell death induced by pharmaceutical ER stress inducing agents. Herein we hypothesize that the anti-HIV drugs target primarily at the Golgi apparatus and dysfunction of Golgi triggers other organelle stress response leading to liver disease development, which is deteriorated by alcohol-induced ER stress response. We propose to: (1) identify specific molecular components of the ER-Golgi traffic machineries that are affected by the anti-HIV drugs and/or alcohol; (2) investigate mechanisms that regulate the drug-induced Golgi stress response; (3) study how the Golgi stress mediates downstream hepatic injury; (4) evaluate cytoprotective effects of therapies targeting the Golgi stress. This project will provide a scientific basis for a better care for HIV/AIDS patients suffering from liver damages resulted from anti-HIV drugs and alcohol abuse.

抗艾滋病毒或HIV- hcv /HBV合并感染药物帮助艾滋病毒/艾滋病患者活得更长、更健康