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Phosphodiesterase 4 mediated pathogenic mechanisms in alcohol associated liver disease

磷酸二酯酶 4 介导的酒精相关性肝病的致病机制

基本信息

批准号：
10877329
负责人：
Leila Gobejishvili
金额：
$ 15.64万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10877329
关键词：
ADD-1 protein Affect Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Animal Model Apoptosis Attenuated Automobile Driving CYP2E1 gene Cell model Cell physiology Cessation of life Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytochrome P450 Data Development Disease Enzymes Ethanol FDA approved Fatty Acids Fatty Liver Genes Goals H19 gene HIF1A gene Heavy Drinking Hepatic Hepatocyte Hydrolysis Impairment In Vitro Inflammatory Injury Knockout Mice Liver Liver diseases MAPK8 gene Mediating Metabolic Mitogen-Activated Protein Kinases PDE4B Pathogenesis Pathogenicity Pathway interactions Patients Phosphoric Monoester Hydrolases Phosphorylation Play Population Process Regulation Role Second Messenger Systems Signal Transduction Specificity Toxic effect Transcriptional Regulation United States Untranslated RNA Up-Regulation Work alcohol effect cell injury genetic manipulation hypoxia inducible factor 1 in vitro Model in vivo inhibitor lipid biosynthesis lipid metabolism liver injury member mortality new therapeutic target novel oxidation phosphatase-1 kinase phosphodiesterase IV phosphoric diester hydrolase preclinical study response transcription factor

项目摘要

2.5% of United States population is affected by alcohol-associated liver disease (ALD), which represents the eighth most common cause of mortality. Despite significant progress in the field, the complex mechanisms driving the onset and progression of ALD are still not fully understood. cAMP is a second messenger that plays a critical role in regulating multiple cellular functions via its effectors (e.g. protein kinase A). Amplitude and duration of cAMP signaling is fine-tuned by phosphodiesterases (PDEs) via cAMP hydrolysis and degradation. Our work has shown that ethanol increases expression of hepatic PDE4 in experimental ALD as well as in alcohol-associated hepatitis (AH) patients’ livers. However, their role in ALD pathogenesis is not clear. We started elucidating the role of PDE4s in ALD by demonstrating that Pde4b plays a critical role in ethanol- mediated impairment of fatty acid β-oxidation and steatosis. We also showed that inhibition of PDE4 activity attenuates liver injury in in vivo and in vitro models of ALD. However, underlying mechanisms of ethanol mediated induction of PDE4 enzymes have not been determined. Moreover, how PDE4 inhibition exerts its beneficial effect on dysregulated lipid metabolism and hepatocytes survival is not fully understood. Our preliminary studies using animal and cell models of ALD identified novel pathways of ethanol and PDE4- mediated regulation of hepatic lipid metabolism and cell injury which have never been examined before. Based on our previous work and preliminary data, our central hypothesis is that ethanol via cytochrome p450 (CYP2E1) mediated increase in hypoxia inducible factor 1 (HIF1α) induces hepatic PDE4 which contributes to dysregulation of hepatic lipid metabolism and injury. The specific objectives of these mechanistic studies are to: Aim 1: Determine the underlying mechanisms of PDE4 upregulation by ethanol in hepatocytes. Aim 2: Determine mechanisms underlying ethanol/PDE4-mediated de novo lipogenesis and hepatic steatosis. Aim 3: Determine the role of MKP1 in ethanol/PDE4-mediated toxicity in hepatocytes. The ultimate goal of this application is to identify not only the mechanisms of PDE4 upregulation, but also the role of PDE4s in the development of ALD. Importantly, we predict that these preclinical studies will provide strong rationale using PDE4 specific inhibitors in the treatment of ALD. Importantly, there are potent PDE4 inhibitors that are already FDA-approved for the treatment of other inflammatory disease processes, and these inhibitors could potentially be repurposed for ALD.

2.5%的美国人口受到酒精相关性肝病（ALD）的影响