The role of Sphingosine Kinase 2 in alcoholic liver disease

鞘氨醇激酶 2 在酒精性肝病中的作用

基本信息

批准号：
9763388
负责人：
Eric Kwun Kwong
金额：
$ 4.49万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
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：
2017-09-25 至 2022-09-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763388
关键词：
ABCC1 gene ABCG2 gene Acute Address Adopted Agonist Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Alcohols Attenuated Bacterial Translocation Bile Acids Binding Cell Culture Techniques Cell Nucleus Cellular Stress Chemicals Chronic Cirrhosis Cytoplasm Data Development Diet Diffusion Disease Progression Disease model Drug Targeting Endotoxins Exhibits FDA approved Fatty Liver Functional disorder G-Protein-Coupled Receptors Genes Growth Hepatic Hepatocyte High Fat Diet Homeostasis Homologous Gene Human In Vitro Inflammation Inflammation Mediators Inflammatory Response Injury Intestinal permeability Intestines Knockout Mice Kupffer Cells Link Lipids Lipopolysaccharides Liver Liver Failure Liver diseases MAP Kinase Gene Mammalian Cell Mediating Membrane Metabolic Diseases Metabolic stress Metabolism Mitochondria Molecular Mus National Institute on Alcohol Abuse and Alcoholism Organoids Oxidative Stress Pathogenesis Pathology Pathway interactions Patients Pattern Play Publishing Regulation Reporting Role Sampling Serum Signal Pathway Signal Transduction Sphingosine Sphingosine-1-Phosphate Receptor Stress Testing Therapeutic Time Tissues Treatment Efficacy Triglycerides Wild Type Mouse alcohol effect autocrine base biological adaptation to stress cell type chronic liver disease clinical application drinking effective therapy endoplasmic reticulum stress fatty acid metabolism gut microbiota in vivo insight lipid mediator lipid metabolism liver inflammation liver injury liver transplantation macrophage mouse model novel nutrient metabolism overexpression paracrine response sphingosine 1-phosphate sphingosine kinase transcriptome sequencing

项目摘要

Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide characterized by the accumulation of lipids within the liver, inflammation and the possibility of progressing to cirrhosis and liver failure. More importantly, there are currently no effective treatments for ALD and liver transplantation remains the only therapeutic option for end stage liver disease. Previous studies have shown that ALD is a result of a combination of endoplasmic reticulum (ER) stress, lipid metabolism dysregulation and inflammation. It has been previously reported that alcohol disrupts gut microbiota homeostasis and causes increased endotoxins that contribute to the pathology of ALD. However, the detailed mechanism(s) underlying ALD and disease progression is poorly understood. We have discovered that sphingosine kinase 2 (SphK2) deficient (SphK2-/-) mice on an alcohol diet exhibit increased steatosis and inflammation compared to wild type mice. Sphingosine 1-phosphate receptor 2 (S1PR2) and SphK2 have been previously shown to play a key role in nutrient metabolism and signaling. However, their roles in alcohol-induced liver injury have not been characterized. The overall objective of this project is to determine the molecular mechanism(s) by which disruption of S1PR2- mediated SphK2 signaling contributes to ALD. Aim 1. First, we will determine the role of S1PR2 and SphK2 in alcohol-induced liver injury. We will examine the effects of alcohol on primary hepatocytes and Kupffer cells derived from S1PR2 deficient (S1PR2-/-) and SphK2-/- mice. We will examine various pathways and mechanisms of injury including hepatic lipid metabolism dysregulation, ER stress and inflammation. For in vivo studies, we will adopt the acute on chronic alcohol mouse model from NIAAA that recapitulates the drinking pattern of human alcoholic liver disease patients to study the effects of S1PR2 and SphK2 deficiency in ALD. We will further characterize the expression patterns of S1PR2 and SphK2 in human ALD liver samples. Aim 2. Second, we will identify potential mechanisms by which S1PR2 and SphK2 protect against alcohol-induced liver injury. We will examine various cellular stress pathways and the role of S1PR2 and SphK2 in regulating inflammatory mediators. Finally, we will evaluate the therapeutic potential of targeting the S1PR2/SphK2- mediated signaling pathway using an S1PR2 chemical agonist CYM-5520 to attenuate alcohol-induced liver injury. Accomplishing these aims could provide important information on the development of effective treatments and drug targets against ALD.

酒精性肝病（ALD）是全球最常见的肝病之一肝脏内脂质的积累，炎症以及发展为肝硬化和肝脏的可能性失败。更重要的是，目前尚无对ALD和肝移植的有效治疗方法末期肝病的唯一治疗选择。先前的研究表明，ALD是A的结果内质网应激，脂质代谢失调和炎症的组合。它有以前有报道说酒精会破坏肠道菌群稳态，并导致内毒素增加这有助于ALD的病理。但是，详细的机制和疾病的基础机制进展知之甚少。我们发现鞘氨醇激酶2（SPHK2）缺乏（SPHK2 - / - ）与野生型小鼠相比，酒精饮食上的小鼠表现出增加的脂肪变性和炎症。鞘氨醇 1-磷酸受体2（S1PR2）和SPHK2先前已被证明在营养中起关键作用代谢和信号传导。但是，尚未表征它们在酒精引起的肝损伤中的作用。这该项目的总体目的是确定S1PR2-中断的分子机制介导的SPHK2信号导致ALD。目标1。首先，我们将确定S1PR2和SPHK2在酒精引起的肝损伤。我们将检查酒精对原发性肝细胞和库普弗细胞的影响源自S1PR2缺陷（S1PR2 - / - ）和SPHK2 - / - 小鼠。我们将检查各种途径，损伤机制，包括肝脂质代谢失调，ER应力和炎症。用于体内研究，我们将对NIAAA的慢性酒精小鼠模型采用急性，以概括饮酒人类酒精性肝病患者的模式研究了ALD中S1PR2和SPHK2缺乏的影响。我们将进一步表征人ALD肝样品中S1PR2和SPHK2的表达模式。目标2。其次，我们将确定S1PR2和SPHK2防止酒精引起的潜在机制肝损伤。我们将检查各种细胞应力途径以及S1PR2和SPHK2在调节中的作用炎症介体。最后，我们将评估靶向S1PR2/SPHK2-的治疗潜力使用S1PR2化学激动剂CYM-5520介导的信号通路来减弱酒精诱导的肝脏受伤。实现这些目标可以提供有关开发有效的重要信息治疗和针对ALD的药物靶标。