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：
10661056
负责人：
Leila Gobejishvili
金额：
$ 35.34万
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/10661056
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，这代表尽管该领域取得了重大进展，但其机制仍然复杂。驱动 ALD 发生和进展的第二信使 cAMP 尚不完全清楚。通过其效应器（例如蛋白激酶 A）在调节多种细胞功能中发挥关键作用。 cAMP 信号传导的持续时间由磷酸二酯酶 (PDE) 通过 cAMP 水解和降解进行微调。我们的工作表明，乙醇可以增加实验性 ALD 以及肝脏 PDE4 的表达。然而，它们在 ALD 发病机制中的作用尚不清楚。通过证明 Pde4b 在乙醇中发挥关键作用，开始阐明 PDE4 在 ALD 中的作用我们还发现，PDE4 活性受到抑制。减轻 ALD 体内和体外模型中的肝损伤然而，乙醇的潜在机制。此外，PDE4 酶的介导诱导尚未确定。对脂质代谢失调和肝细胞存活的有益影响尚不完全清楚。使用 ALD 动物和细胞模型进行的初步研究确定了乙醇和 PDE4- 的新途径介导的肝脏脂质代谢和细胞损伤的调节，这是以前从未研究过的。根据我们之前的工作和初步数据，我们的中心假设是乙醇通过细胞色素 p450 (CYP2E1) 介导的缺氧诱导因子 1 (HIF1α) 增加会诱导肝 PDE4，从而导致肝脏脂质代谢失调和损伤。这些机制研究的具体目标是：目标 1：确定乙醇在肝细胞中上调 PDE4 的潜在机制。目标 2：确定乙醇/PDE4 介导的从头脂肪生成和肝脏的潜在机制脂肪变性。目标 3：确定 MKP1 在乙醇/PDE4 介导的肝细胞毒性中的作用。该应用的最终目标不仅是确定 PDE4 上调的机制，而且是确定 PDE4 上调的机制。重要的是，我们预测这些临床前研究将提供 PDE4 在 ALD 发展中的作用。使用 PDE4 特异性抑制剂治疗 ALD 的有力理由重要的是，存在有效的 PDE4。已经获得 FDA 批准用于治疗其他炎症性疾病过程的抑制剂，以及这些抑制剂有可能重新用于 ALD。