Phosphodiesterase 4B Inhibition as a Therapeutic Target for Alcohol-associated Liver Disease

磷酸二酯酶 4B 抑制作为酒精相关性肝病的治疗靶点

基本信息

批准号：
10354185
负责人：
Virender Kumar
金额：
$ 39.02万
依托单位：
UNIVERSITY OF TOLEDO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-25 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10354185
关键词：
Abdominal Pain Abstinence Adenylate Cyclase Adrenal Cortex Hormones Adverse effects Alcohol consumption Alcoholic Liver Diseases Alcohols Antibiotics Antiinflammatory Effect Binding Brain Cells Cholestasis Cicatrix Circulation Cirrhosis Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Cyclic Nucleotides Data Dendritic Cells Deposition Development Diarrhea Diet Disease Progression Drug Delivery Systems Drug Kinetics Dyspepsia Endoplasmic Reticulum Endotoxins Enzymes Ethanol Ethanol Metabolism Fatty Liver Fatty acid glycerol esters Fibrosis Generations Genetic Transcription Health Heavy Drinking Hepatic Hepatic Stellate Cell Hepatocyte Histology Human Hydrophobicity Immune In Vitro Inflammation Inflammatory Inflammatory Response Injury Intestinal permeability Intestines Kupffer Cells Lipopolysaccharides Liver Liver Cirrhosis Liver Failure Liver Fibrosis Liver diseases Macrophage Mediating Modeling Morbidity - disease rate Mus NADH NF-kappa B National Institute on Alcohol Abuse and Alcoholism Nausea Organ PDE4B Permeability Pharmaceutical Preparations Play Polyethylene Glycols Process Production Reaction Role Rolipram Second Messenger Systems Signal Transduction Solid Specificity Superoxides TLR4 gene TNF gene Tissues Toll-like receptors Toxic effect Treatment Efficacy United States Vomiting alcohol effect alcohol prevention antagonist blood-brain barrier crossing cytokine drug efficacy endoplasmic reticulum stress gadolinium chloride gastrointestinal gut bacteria hepatocyte injury improved in vivo inhibitor lipid nanoparticle liver inflammation liver injury liver transplantation monocyte mortality mouse model nanoparticle non-alcoholic fatty liver disease novel oxidative damage pharmacologic phosphodiesterase 6 phosphodiesterase IV phosphoric diester hydrolase prevent problem drinker recruit side effect small molecule therapeutic evaluation therapeutic target

项目摘要

PROJECT SUMMARY Alcohol-associated liver disease (ALD) is a significant health problem caused by excessive alcohol consumption. ALD is generally discovered in association with fatty liver, steatosis, or fibrosis progression, leading to cirrhosis. Unfortunately, there is no approved drug for ALD, and the current therapies rely on abstinence, immune suppressants like corticosteroids, or liver transplantation in case of advanced cirrhosis. Studies suggest that inflammation plays a significant role in ALD initiation and progression. Kupffer cells (KCs), the residing macrophages in the liver, are mainly involved in hepatic inflammatory reactions. KCs, upon contact with injured hepatocytes or gut bacterial endotoxins such as lipopolysaccharides (LPS), get activated and secrete inflammatory cytokines, including TNF-α and start the inflammation. Pharmacological inhibition of KCs by small molecules such as gadolinium chloride or decreasing intestinal bacterial load with antibiotics is shown to prevent liver injury and ALD progression. Cyclic adenosine monophosphate (cAMP) signaling plays a significant role in dampening hepatic injury and steatosis. Alcohol is known to increase the expression of cAMP degrading enzyme phosphodiesterase 4 (PDE4). The upregulated PDE4 decreases the cAMP levels and induces liver inflammation/injury. PDE4 inhibitors have been investigated to inhibit macrophage recruitment and activation in ALD; however, the current PDE4 inhibitors such as rolipram and roflumilast are associated with severe side effects, including nausea, vomiting, diarrhea, and dyspepsia. This study aims to inhibit PDE4B activity by novel inhibitor KVA-D-88 in alcohol-induced steatosis. Our preliminary data show that KVA-D-88 is a potent and selective PDE4B inhibitor with a suitable pharmacokinetic profile. The development of highly selective PDE4B inhibitors such as KVA-D-88 directly applies to human ALD. However, PDE4B inhibition in other organs, such as the brain, is known to produce severe side effects. Therefore, there is a need for KC-specific drug delivery to enhance the drug efficacy and specificity. We will develop KVA-D-88 nanoparticles for liver-specific PDE4B inhibition. Our specific aims are Aim 1 to establish the role of PDE4B inhibitor KVA-D-88 in ALD in vitro and in vivo. In this aim, we will determine the specificity of KVA-D-88 to inhibit PDE4B isotype compared to PDE4D isotype in alcohol-induced primary KCs, hepatocytes, and hepatic stellate cells (HSCs). Next, we will evaluate the effect of KVA-D-88 mediated PDE4B inhibition on cAMP signaling, TNF-α induced ER stress, and ethanol- induced toxicity in the modified NIAAA mouse model. Aim 2. Formulate and characterize KCs targeted KVA- D-88 loaded polyethylene glycol (PEG) decorated solid lipid nanoparticles (SLNs). In this aim, we will develop and characterize KCs targeted PEG-SLNs loaded with KVA-D-88. Next, we will evaluate the therapeutic efficacy of KVA-D-88 loaded SLNs in the NIAAA model. This project is highly significant as it could provide us with ALD therapy and a potential platform for nonalcoholic fatty liver disease (NAFLD) and cholestasis-induced liver fibrosis.

项目概要酒精相关性肝病（ALD）是由过量饮酒引起的严重健康问题。 ALD 通常与脂肪肝、脂肪变性或纤维化进展相关，从而导致肝硬化。不幸的是，目前还没有批准治疗 ALD 的药物，目前的治疗方法依赖于戒酒、免疫研究表明，在晚期肝硬化的情况下使用皮质类固醇等抑制剂或肝移植。炎症在 ALD 的发生和进展中发挥着重要作用。肝脏中的巨噬细胞在接触受伤的 KC 时主要参与肝脏炎症反应。肝细胞或肠道细菌内毒素，如脂多糖 (LPS)，被激活并分泌炎症细胞因子，包括 TNF-α，通过小 KC 启动炎症。氯化钆等分子或用抗生素减少肠道细菌负荷被证明可以预防环磷酸腺苷 (cAMP) 信号在肝损伤和 ALD 进展中发挥着重要作用。已知酒精会增加 cAMP 降解酶的表达，从而抑制肝损伤和脂肪变性。磷酸二酯酶 4 (PDE4) 上调的 PDE4 会降低 cAMP 水平并诱导肝损伤。 PDE4 抑制剂已被研究可抑制巨噬细胞的募集和激活。然而，目前的 PDE4 抑制剂如咯利普兰和罗氟司特与严重的副作用有关。本研究旨在通过新型药物抑制 PDE4B 活性。抑制剂 KVA-D-88 在酒精诱导的脂肪变性中的作用我们的初步数据表明 KVA-D-88 是一种有效且有效的药物。具有合适药代动力学特征的选择性 PDE4B 抑制剂开发高选择性 PDE4B。 KVA-D-88等抑制剂直接适用于人类ALD，但PDE4B在其他器官中具有抑制作用。众所周知，KC 会产生严重的副作用，因此需要针对 KC 的药物递送。我们将开发针对肝脏特异性PDE4B的KVA-D-88纳米颗粒。我们的具体目标是目标 1：确定 PDE4B 抑制剂 KVA-D-88 在体外和 ALD 中的作用。为此，我们将确定 KVA-D-88 与 PDE4D 相比抑制 PDE4B 同种型的特异性。接下来，我们将评估酒精诱导的原代 KC、肝细胞和肝星状细胞 (HSC) 中的同型。 KVA-D-88 介导的 PDE4B 抑制对 cAMP 信号、TNF-α 诱导的 ER 应激和乙醇的影响在改良的 NIAAA 小鼠模型中诱导毒性目标 2. 制定并表征针对 KVA- 的 KC。 D-88 负载聚乙二醇 (PEG) 修饰的固体纳米脂质颗粒 (SLN)。开发并表征负载 KVA-D-88 的 KC 靶向 PEG-SLN 接下来，我们将评估治疗效果。 KVA-D-88 高负载 SLN 在 NIAAA 模型中的功效该项目意义重大，因为它可以为我们提供帮助。 ALD 疗法以及非酒精性脂肪性肝病 (NAFLD) 和胆汁淤积引起的潜在平台肝纤维化。