Role of microRNA_21 in acetaminophen-induced acute liver failure

microRNA_21在对乙酰氨基酚诱导的急性肝衰竭中的作用

• 批准号: 9433645
• 负责人: Damian G. Romero
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9433645
• 关键词: Ablation; Acetaminophen; Acetylcysteine; Acute; Acute Liver Failure; Adolescent and Young Adult; Affect; Ammonia; Behavior; Biochemical; Blood Coagulation Disorders; Cessation of life; Child; Clinic; Clinical Management; Cysteine; Data; Development; Diagnosis; Down-Regulation; Drug Metabolic Detoxication; Encephalopathies; Energy Metabolism; Enzymes; Experimental Animal Model; Failure; Fibrosis; Foundations; Genetic; Glucose; Glutamate-Ammonia Ligase; Health; Hepatic; Hepatocyte; Hepatotoxicity; Human; Individual; Intoxication; Knowledge; Lead; Life; Liver; Mediating; Messenger RNA; MicroRNAs; Mission; Molecular; Mus; Nature; Organism; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Play; Proteins; Public Health; Recovery; Research; Resistance; Role; Serum; Signal Pathway; Small RNA; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Transgenic Mice; United States National Institutes of Health; Untranslated RNA; Virus Diseases; Xenobiotic Metabolism; acetaminophen overdose; acute liver injury; attenuation; base; beta catenin; disability; hepatic necrosis; innovation; liver biopsy; liver function; liver inflammation; liver injury; liver transplantation; mortality; novel therapeutic intervention; outcome forecast; overexpression; protective effect; therapeutic target

Acute liver failure (ALF) is characterized by severe and sudden loss of hepatocellular function in patients with previously normal liver function which may lead to multiorgan system failure and death. In the US, drug- induced liver injury is the main cause of ALF, and acetaminophen (APAP) intoxication accounts for ~50% of ALF cases. APAP-induced ALF disproportionally affects children, adolescents and young adults. N-acetyl- cysteine is the only currently available therapy for APAP-induced ALF; however, it is not completely effective with a mortality rate of 30% and another 10% requiring liver transplant. Therefore, alternative or complemen- tary pharmacological therapies are desperately needed for individuals, especially children, suffering from APAP-induced ALF. MicroRNAs (miRNAs) have been implicated in liver inflammation, fibrosis, and viral infection. MiRNAs are highly attractive therapeutic targets on their way into the clinic, but the role of miRNAs as therapeutic agents in APAP-induced ALF remains unexplored. MicroRNA-21 (miR-21) is an attractive candi- date because it is one of the most highly expressed hepatic miRNAs and is dynamically regulated by APAP overdose. Furthermore, in patients with spontaneous recovery from ALF, miR-21 expression is decreased in liver biopsies, strongly suggesting that reduction of hepatic miR-21 levels may be a valid therapeutic approach for APAP-ALF. One mechanism by which miR-21 reduction is protective against APAP-ALF may be due to changes in liver zonation. Liver zonation is critical for ammonia detoxification, glucose/ energy metabolism, and xenobiotic metabolism. Pharmacological manipulation of specific hepatic miRNAs could lead to transient liver zonation disruption that may protect against APAP-induced ALF. We have preliminary data that miR-21 genetic ablation in mice protects against APAP-induced ALF, with attenuation of APAP-mediated increases in serum hepatic enzymes and reduced liver necrosis. Furthermore, miR-21 over-expression in transgenic mice exacerbates the APAP-induced liver injury. We also have preliminary data that miR-21 is preferentially expressed in periportal hepatocytes. In addition, miR-21 ablation disrupts the expression pattern of hepatic glutamine synthetase, suggesting that the lack of miR-21 leads to a periportal-like liver phenotype that may also contribute to the protective effect of miR-21 downregulation in APAP-induced ALF. Based on these exciting preliminary data, we propose to test the central hypothesis that “miR-21 regulates liver zonation, and downregulation of miR-21 leads to a periportal-like liver phenotype that protects against APAP-induced hepatotoxicity.” This hypothesis will be tested in the following specific aims: 1) To test the hypothesis that miR-21 ablation protects against, while miR-21 over-expression exacerbates, APAP-induced hepatotoxicity; 2) To test the hypothesis that acute pharmacological downregulation of miR-21 protects against APAP-induced acute liver failure; 3) To test the hypothesis that miR-21 is preferentially expressed in periportal hepatocytes and regulates liver zonation thereby modulating APAP-induced hepatotoxicity.

急性肝功能衰竭(ALF)的特征是严重和突然的肝细胞功能丧失 以前肝功能正常，可能导致多器官系统衰竭和死亡。在美国，毒品- 肝损伤是ALF的主要原因，对乙酰氨基酚(APAP)中毒约占ALF的50% ALF案件。APAP诱导的ALF对儿童、青少年和青壮年的影响不成比例。N-乙酰基- 半胱氨酸是目前治疗APAP所致ALF的唯一有效方法；然而，它并不完全有效。 死亡率为30%，另有10%需要肝脏移植。因此，替代或补充- 急切需要药物治疗的人，特别是儿童，患有 APAP诱导的ALF。MicroRNAs(MiRNAs)与肝脏炎症、纤维化和病毒有关 感染。MiRNAs是临床上极具吸引力的治疗靶点，但miRNAs的作用 作为APAP诱导的ALF的治疗药物，目前尚不清楚。MicroRNA-21(miR-21)是一种极具吸引力的糖蛋白。 因为它是肝脏中表达最高的miRNAs之一，并受APAP动态调节 服药过量。此外，在ALF自发恢复的患者中，miR-21的表达在 肝活检，强烈提示降低肝脏miR-21水平可能是一种有效的治疗方法 适用于APAP-ALF。MiR-21降低对APAP-ALF具有保护作用的一个机制可能是由于 肝脏分区的改变。肝脏分区对于氨解毒、葡萄糖/能量代谢和 异种生物代谢。对特定肝脏miRNAs的药理学操作可能导致一过性肝 可防止APAP诱导的ALF的分区破坏。我们有初步数据表明miR-21基因 消融小鼠对APAP诱导的ALF具有保护作用，并减弱了APAP介导的血清升高 降低肝脏酶活性，减少肝脏坏死。此外，miR-21在转基因小鼠中过表达 加重APAP诱导的肝损伤。我们也有初步数据表明miR-21优先 在门静脉周围肝细胞中表达。此外，miR-21消融还扰乱了肝脏的表达模式 谷氨酰胺合成酶，提示miR-21的缺失导致门脉周围样的肝脏表型，可能 也参与了miR-21在APAP诱导的ALF中下调的保护作用。基于这些 令人振奋的初步数据，我们建议测试的中心假设，“miR-21调节肝脏分区，和 MiR-21的下调导致门脉周围样的肝脏表型，对APAP诱导的肝脏具有保护作用 肝脏毒性。“这一假说将在以下具体目标中进行检验：1)检验假说 MIR-21消融对APAP诱导的肝毒性有保护作用，而miR-21的过表达加剧了APAP的肝毒性； 验证急性药物下调miR-21对APAP诱导的保护作用的假说 急性肝功能衰竭；3)检验miR-21优先在门脉周围肝细胞表达的假设 并调节肝脏分区，从而调节APAP所致的肝毒性。