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 合并感染药物可帮助 HIV/AIDS 患者活得更长久、更健康然而，艾滋病毒药物常常会引起副作用，尽管大多数副作用来自艾滋病毒。药物是可以控制的，但有一些药物对肝脏的损害可能会非常严重，甚至危及生命更糟糕的是，近一半的艾滋病毒感染者酗酒/饮酒或酗酒。多种药物滥用问题，不仅影响患者抗艾滋病治疗的依从性，还会恶化抗病毒药物引起的肝毒性，导致更高的发病率和死亡率。肝毒性的分子机制和潜在的治疗靶点正在研究中我们和其他人之前的深入研究表明内质网（ER）压力会导致艾滋病毒蛋白酶抑制剂和/或酒精滥用引起的肝细胞死亡，然而，动物模型和患者的脂肪性肝炎和肝硬化的治疗可确保适当的 ER。体内平衡，例如化学伴侣、抗氧化剂、自噬诱导剂的应用，或保护性 ER 信号通路的选择性增强仅在多种疾病中产生部分效果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其中我们最近的研究揭示了抗艾滋病毒药物/或酒精引起的强烈肝毒性。某些 HIV 蛋白酶抑制剂对 ER-高尔基体运输和高尔基体完整性的影响装置，其发生早于内质网应激反应并导致细胞死亡增加与药物 ER 应激诱导剂诱导的细胞死亡相比。抗艾滋病毒药物主要针对高尔基体和高尔基体功能障碍引发其他细胞器应激反应，导致肝病恶化我们建议：（1）确定酒精诱导的内质网应激反应的特定分子成分。 (2)调查受抗HIV药物和/或酒精影响的ER-高尔基体交通机器；调节药物引起的高尔基体应激反应的机制；（3）研究高尔基体应激反应的机制；介导下游肝损伤；（4）评估靶向治疗的细胞保护作用高尔基压力。该项目将为更好地护理艾滋病毒/艾滋病患者提供科学依据。因抗艾滋病毒药物和酗酒而遭受肝损伤。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adverse Effects of Anti-Covid-19 Drug Candidates and Alcohol on Cellular Stress Responses of Hepatocytes.

抗 Covid-19 候选药物和酒精对肝细胞细胞应激反应的不利影响。

DOI：
发表时间：
2022-06
期刊：
影响因子：
5.1
作者：
Khalatbari, Atousa;Aghazadeh, Zahra;Ji, Cheng
通讯作者：
Ji, Cheng

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors.

与 HIV/SARS-CoV-2 蛋白酶抑制剂相关的肝毒性的分子因素和途径。

DOI：
发表时间：
2023-04-27
期刊：
影响因子：
5.6
作者：
Ji; Cheng
通讯作者：
Cheng

Dissecting the Role of Disturbed ER-Golgi Trafficking in Antivirals and Alcohol Abuse-Induced Pathogenesis of Liver Disorders.

剖析内质网高尔基体运输紊乱在抗病毒药物和酒精滥用引起的肝脏疾病发病机制中的作用。

DOI：
发表时间：
2017
期刊：
影响因子：
0
作者：
Ji; Cheng
通讯作者：
Cheng

A Hepatocyte-Mimicking Antidote for Alcohol Intoxication.

一种模拟肝细胞的酒精中毒解毒剂。

DOI：
发表时间：
2018-05
期刊：
影响因子：
0
作者：
Xu, Duo;Han, Hui;He, Yuxin;Lee, Harrison;Wu, Di;Liu, Fang;Liu, Xiangsheng;Liu, Yang;Lu, Yunfeng;Ji, Cheng
通讯作者：
Ji, Cheng

Ritonavir and Lopinavir Suppress RCE1 and CAAX Rab Proteins Sensitizing the Liver to Organelle Stress and Injury.

利托那韦和洛匹那韦抑制 RCE1 和 CAAX Rab 蛋白，使肝脏对细胞器应激和损伤敏感。