Molecular Regulation of Hepatic Transporters

肝脏转运蛋白的分子调控

• 批准号: 7256906
• 负责人: SAUL J. KARPEN
• 金额: $ 29.13万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256906
• 关键词: ABCC1 gene; Abbreviations; Acute; Acute-Phase Reaction; Anions; Anti-Inflammatory Agents; Attenuated; Bile Acids; Bile fluid; Binding; Carrier Proteins; Cations; Cholestasis; Cholesterol; Cholic Acid; Cholic Acids; Chronic; Curcumin; Data; Deoxycholic Acid; Dexamethasone; Digestive System Disorders; Direct Repeats; Effectiveness; Enhancers; Functional disorder; Gene Expression; Gene Proteins; Genes; Glucocorticoids; Glutathione S-Transferase; Goals; Green Fluorescent Proteins; Hepatic; Hepatobiliary; Hepatocyte; In Vitro; Individual; Inflammation; Inflammatory; Interleukin-1; Intervention; Knock-out; Ligands; Link; Lipopolysaccharides; Lithocholic Acid; Liver; Liver diseases; Location; MAPK8 gene; MAPK9 gene; MG132; Maps; Mediating; Mediator of activation protein; Membrane; Membrane Proteins; Mitogen-Activated Protein Kinases; Modeling; Modification; Molecular; Molecular Target; Multi-Drug Resistance; Mus; Nuclear; Nuclear Export; Nuclear Receptors; P-Glycoproteins; Pathway interactions; Phospholipids; Phosphorylation; Phosphotransferases; Physiological; Physiology; Post-Translational Protein Processing; Post-Translational Regulation; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Pump; RXR; Reaction; Regulation; Research Personnel; Retinoic Acid Receptor; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic Intervention; Time; Transcription Coactivator; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Ubiquitin; Ubiquitination; Zalcitabine; alitretinoin; base; bile acid transporter; bile salts; chicken DcoHalpha protein; cytokine; design; extracellular; functional disability; hepatocyte nuclear factor; human TNF protein; in vitro Model; in vivo; inhibitor/antagonist; macromolecular assembly; member; multicatalytic endopeptidase complex; non-genomic; novel therapeutics; polypeptide; pregnane X receptor; promoter; protein activation; protein expression; receptor; research study; response; rosiglitazone; stress-activated protein kinase 1; transcription factor

DESCRIPTION (provided by applicant): One of the central features of the hepatic response to inflammation is the suppression of a broad array of core physiological functions, including those essential to maintaining hepatobiliary transport of bile acids. In addition to post-translational regulation of transporter protein membrane expression and function, inflammation-based cell signaling pathways act on nuclear targets to transcriptionally suppress the expression of the essential bile acid transporters Ntcp and Bsep. The central Type II NR superfamily member and heterodimer partner RXRalpha is a major transcriptional activator of these two genes, and its nuclear activity is rapidly suppressed by inflammation-based cell signaling. Reduced RXRalpha target gene expression leads to multiple functional impairments and damage to hepatocytes. How cell signaling pathways suppress RXRalpha function is unknown, and forms the basis for the explorations and interventions proposed in this application. The overall unifying hypothesis is that inflammatory cell signaling pathways reduce nuclear activity of RXRalpha via a coordinated cascade of post-translational modification, nuclear export and proteasomal degradation. The following four aims will determine the underlying physiology and pathophysiology of inflammation-mediated cholestasis and explore novel therapeutics. Aim 1: Define the molecular mechanisms mediating IL-1beta-induced nuclear export of RXRalpha. Aim 2: Determine roles for ubiquitination and proteasomal degradation of RXRalpha in response to IL-1beta- induced signaling pathways. Aim 3: Explore crosstalk between bile acid and IL-1beta-mediated pathways that modify RXRalpha function. Aim 4: Investigate the effects of anti-inflammatory agents on transporter gene and protein expression in the IPS model of hepatic inflammation. It is through a combined in vitro and in vivo approach that we can explore the mechanisms, mediators, and potential therapeutic interventions aimed at restoring RXRalpha function, hepatobiliary transporter function, and bile flow, in the setting of inflammation-mediated cell signaling in liver. The ultimate goal of these studies is to provide rational molecular targets for the testing of therapies specifically designed to interfere with the damaging consequences of inflammation-mediated pathways, which are engaged in nearly all forms of acute and chronic liver diseases.

描述（由申请方提供）：肝脏对炎症反应的中心特征之一是抑制广泛的核心生理功能，包括维持胆汁酸肝胆转运所必需的功能。除了转运蛋白膜表达和功能的翻译后调节之外，基于炎症的细胞信号传导途径作用于核靶点以转录抑制必需胆汁酸转运蛋白Ntcp和Bsep的表达。中心II型NR超家族成员和异二聚体伴侣RXR α是这两个基因的主要转录激活因子，并且其核活性被基于炎症的细胞信号传导迅速抑制。RXR α靶基因表达减少导致多种功能障碍和肝细胞损伤。细胞信号通路如何抑制RXR α功能尚不清楚，并形成了本申请中提出的探索和干预的基础。总体统一的假设是，炎症细胞信号传导途径通过翻译后修饰、核输出和蛋白酶体降解的协调级联降低RXR α的核活性。以下四个目标将确定炎症介导的胆汁淤积的潜在生理学和病理生理学，并探索新的治疗方法。目的1：阐明IL-1 β诱导RXR α核输出的分子机制。目的2：确定RXR α的泛素化和蛋白酶体降解在IL-1 β诱导的信号通路中的作用。目的3：探讨胆汁酸和IL-1 β介导的调节RXR α功能的通路之间的相互作用。目的4：观察抗炎药对IPS肝脏炎症模型中转运蛋白基因和蛋白表达的影响。正是通过体外和体内相结合的方法，我们可以探索机制，介质和潜在的治疗干预措施，旨在恢复RXR α功能，肝胆转运蛋白功能和胆汁流量，在肝脏炎症介导的细胞信号传导的设置。这些研究的最终目标是为专门设计用于干扰炎症介导的途径的破坏性后果的疗法的测试提供合理的分子靶点，炎症介导的途径参与几乎所有形式的急性和慢性肝病。