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：
10160856
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 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160856
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 multidrug abuse 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HIV或HIV-HCV/HBV共同感染药物可帮助艾滋病毒/艾滋病患者寿命更长，更健康居住。但是，HIV药物通常会引起副作用。虽然艾滋病毒的大多数副作用药物是可以控制的，肝脏损害的一些可能非常严重，生命威胁。更糟糕的是，几乎一半的艾滋病毒感染患者滥用/食用酒精或多个滥用药物的问题，不仅会损害患者对抗HIV疗法的遵守还会恶化抗病毒诱导的肝毒性，从而导致更大的发病率和死亡率。分子机制和肝毒性基础的潜在治疗靶标在激烈的调查。我们和其他人的先前研究表明内质网（ER）压力有助于HIV蛋白抑制剂和/或酒精滥用引起的肝细胞死亡，动物模型和患者的脂肪性肝炎和肝硬化。但是，确保适当的疗法稳态，例如化学伴侣，抗氧化剂，自噬影响者或保护性ER信号通路的选择性增强仅在各种IN中产生部分影响体外和体内模型系统，这表明其他更精确的细胞靶标也参与抗HIV药物和/或酒精诱导的肝毒性。我们最近的研究表明某些HIV蛋白抑制剂对Golgi的ER高尔基运输和完整性的影响仪器发生的设备比ER应力反应早，并导致细胞死亡增加与药物ER应力诱导的药物诱导的细胞死亡相比。在这里我们假设抗HIV药物靶向高尔基体和高尔基的功能障碍触发其他细胞器压力反应导致肝病发育，这是确定的通过酒精引起的ER应力反应。我们建议：（1）确定特定的分子成分受抗HIV药物和/或酒精影响的ER-Golgi交通机器；（2）调查调节药物引起的高尔基应激反应的机制；（3）研究高尔基人如何应力介导下游的肝损伤；（4）评估靶向疗法的细胞保护作用高尔基压力。该项目将为艾滋病毒/艾滋病患者提供更好的护理提供科学基础受抗HIV药物和酒精滥用造成的肝损害。