Liver-specific glucocorticoid action in alcoholic liver disease.

项目摘要 酒精性肝炎(AH)是一种炎症、胆汁淤积和肝功能衰竭的综合征，在 美国。唯一可以适度提高存活率的治疗方法是糖皮质激素(GC)， 几十年来一直没有成功研发出新药。GCS的基本原理是激活糖皮质激素 受体(GR)阻断急性脑出血患者的细胞毒性和炎症通路。然而，GC治疗急性酒精性肝炎 引起严重的副作用，主要是由于GCs对肝外组织的不良影响。因此，肝脏特异性 激活GR可能通过减少GC的肝外副作用而显著改善AH的治疗。一个 酒精性肝病(ALD)肝脏特异性GR靶向治疗的先决条件是充分了解GR的作用 肝特异性GR缺乏和激活在ALD发病机制中的作用我们的长期目标是开发小说 阿尔茨海默病的治疗方法。胆汁酸(BA)-药物偶联物已成功开发用于肝脏特异性药物 通过肝脏特异的BA转运体Na+-牛磺胆酸共转运多肽(NTCP)进行靶向。我们有 地塞米松和地塞米松的胆酸结合物(DEX-CA)的合成 验证了它们依赖于NTCP的细胞摄取和活性。此R21提案的目标是开发 这些新的DEX-CA作为ALD的新药候选，并揭示了肝脏特异性缺陷和 GR激活调节肝脏基因表达、代谢动态平衡和ALD发病机制。我们的数据 挖掘发现，AH人肝脏和肝细胞特异性GR基因敲除的成年小鼠的肝脏具有 某些关键的GR靶向细胞保护和抗炎基因的高度相似下调，以及 在我们的小鼠研究中，肝脏GR信号受损与胆汁淤积性肝损伤有关。中环 假设肝细胞中的GR在预防急性肝炎和酒精性肝硬变中起关键作用。通过 降低肝外组织GCs的不良反应，发挥细胞保护和抗肿瘤作用 对肝脏的炎症效应，NTCP介导的肝脏特异性GR激活剂将得到很大的改善 治疗急性酒精性肝炎和酒精性肝硬变的新疗法。目标1将描述和优化 两类地塞米松的体内外药代动力学和药效学研究 肝脏特异性GR激活。目标2将描绘肝脏特异性基因剂量依赖的GR缺陷 DEX-CA激活GR对酒精性肝炎和酒精性肝硬变模型小鼠的酒精性肝病有影响。这项建议 由于其概念上的进步和最新的方法，它具有很高的创新性。这项研究将得到进一步发展 高度创新的DEX-CA结合物作为新的候选药物和第一个治疗肝脏的药理工具- GR的特异性激活。它将揭示基因剂量依赖的GR缺乏症和肝脏- GR在调节肝脏转录组、代谢动态平衡和ALD发病机制中的特异性激活 DEX-CA结合物的作用是否依赖于肝细胞内的GR。这将有助于开发 DEX-cas通过肝脏特异性激活糖皮质激素受体治疗酒精性肝炎和酒精性肝硬变。

Project Summary Alcoholic hepatitis (AH) is a syndrome of inflammation, cholestasis, and liver failure with worsening profile in the US. The only available drug therapy for AH that moderately improve survival is glucocorticoids (GCs), with no new drugs successfully developed for decades. The rationale of GCs is to activate the glucocorticoid receptor (GR) to block cytotoxic and inflammatory pathways in AH patients. However, GC treatment of AH causes serious side effects, largely due to GCs’ adverse effects on extrahepatic tissues. Thus, liver-specific activation of GR may markedly improve AH therapy by minimizing GC’s extrahepatic adverse effects. A prerequisite for liver-specific GR targeting for alcoholic liver disease (ALD) is to fully understand the roles of liver-specific deficiency and activation of GR in ALD pathogenesis. Our long-term goal is to develop novel therapies for ALD. Bile acid (BA)-drug conjugates have been successfully developed for liver-specific drug targeting via the liver-specific BA transporter Na+-taurocholate cotransporting polypeptide (NTCP). We have successfully synthesized two first-in-class cholic acid (CA) conjugates of dexamethasone (DEX-CA) and verified their NTCP-dependent cellular uptake and activity. The objective of this R21 proposal is to develop these novel DEX-CAs as new drug candidates for ALD, and uncover how liver-specific deficiency and activation of GR regulate hepatic gene expression, metabolic homeostasis, and ALD pathogenesis. Our data mining found that AH human livers and livers from adult mice with hepatocyte-specific knockout of GR had highly similar down-regulation of certain key GR-target cytoprotective and anti-inflammatory genes, and impaired hepatic GR signaling was associated with cholestatic liver injury in our mouse studies. The central hypothesis is that GR in hepatocytes plays a key role in protecting against AH and alcoholic cirrhosis. By decreasing the adverse effects of GCs in extrahepatic tissues and exerting cytoprotective and anti- inflammatory effects on the liver, NTCP-mediated liver-specific GR activators will be a much-improved therapy for AH and a novel therapy for alcoholic cirrhosis. Aim 1 will characterize and optimize the pharmacokinetics and pharmacodynamics of the two classes of DEX-CAs in vitro and in vivo for maximum liver-specific GR activation. Aim 2 will delineate how liver-specific gene-dosage-dependent GR deficiency and activation of GR by DEX-CA affects ALD in mouse models of AH and alcoholic cirrhosis. This proposal is highly innovative because of its conceptual advances and up-to-date approaches. This study will develop highly innovative DEX-CA conjugates as new drug candidates and the first pharmacological tool for liver- specific activation of GR. It will uncover novel roles of gene-dosage-dependent GR deficiency and liver- specific activation of GR in regulating hepatic transcriptome, metabolic homeostasis and ALD pathogenesis, and whether the DEX-CA conjugate's actions are dependent on GR in hepatocytes. This will help develop novel improved therapy for AH and alcoholic cirrhosis via liver-specific activation of GR by DEX-CAs.