Heat shock protein 90 in alcoholic liver disease: targeting macrophage Function

酒精性肝病中的热休克蛋白 90：靶向巨噬细胞功能

基本信息

批准号：
10522788
负责人：
Pranoti Mandrekar
金额：
$ 55.78万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522788
关键词：
Acetylation Affect Alcohol abuse Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Bioenergetics Cell Nucleus Cellular Stress Chromatin Chronic Cirrhosis Data Disease model Economic Burden Endoplasmic Reticulum Endothelial Cells Enzymes Epigenetic Process Ethanol Fatty Liver Funding Future GRP78 gene Gene Expression Genes Glucose Transporter Glycolysis HIF1A gene HSF1 HSP 90 inhibition Health Heat-Shock Proteins 90 Hepatocyte Hexokinase 2 Human In Vitro Inflammasome Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Investigation Kupffer Cells Liver Liver diseases Macrophage Activation Malignant Neoplasms Mediating Mediator of activation protein Messenger RNA Metabolic Metabolic Pathway Metabolism Molecular Chaperones Mus Myelogenous Pathogenicity Pathway interactions Patients Peripheral Blood Mononuclear Cell Primary carcinoma of the liver cells Protein Isoforms Proteins Proteome Receptor Signaling Reporting Resolution Role SLC2A1 gene Signal Transduction Signaling Molecule Steatohepatitis Stress TLR4 gene TREM2 gene activating transcription factor 3 aerobic glycolysis clinical development endoplasmic reticulum stress extracellular vesicles immune activation in vivo inhibitor lipid metabolism liver inflammation liver injury macrophage monocyte nanoparticle novel novel therapeutics paralogous gene prevent proteostasis therapeutic target tissue injury

项目摘要

ABSTRACT Liver immune cell activation is central to alcohol associated liver disease (ALD) and is poorly understood. The protein homeostasis network/pathways are crucial in safeguarding the cellular proteome from cellular stress. Amongst these, proteostasis mediator HSP90 is widely studied and extensively explored as a therapeutic target in cancer. We reported two isoforms of HSP90, HSP90AA1 (stress inducible cytoplasmic HSP90) and HSP90B1/GP96 (Endoplasmic reticulum paralog of HSP90) are important in ALD. These studies point to a pathophysiological role for HSP90 in ALD. Studies during the last funding period of this project established that liver targeting of HSP90 inhibitor 17-DMAG using nanoparticles in ALD can prevent and reverse liver injury, GP96/HSP90B1 deficiency in macrophages facilitates resolution of liver inflammation and ALD, M-TLR4 deficient mice are not protected from ALD, inhibition of HSP90 reduced NLRP3 inflammasome activity decreasing IL-1β protein and HSF1 partially contributes to reduced pro-inflammatory signaling, whereas deficiency of HSF1 did not protect from ALD, suggesting that HSF1 does not contribute to resolution of ALD. In the next project period we will investigate mechanisms mediated by HSP90AA1 and HSP90B1/GP96 in alcohol induced liver macrophage activation resulting in ALD. We propose that HSP90 induces inflammation by alternate mechanisms (independent of HSP90/TLR4 axis), for instance macrophage aerobic glycolysis via epigenetic mechanisms or HIF1α. In our preliminary data, we found that HSP90AA1 is detected in the nucleus in ALD and its inhibition can modulate expression of chromatin-modifying enzymes. Pilot data also reveal that inhibition of HSP90AA1 reduces alcohol mediated induction of glucose transporter (SLC2a1/GLUT1) and hexokinase II, two important mediators of glycolysis, suggesting a role for HSP90 in metabolic programming of M1 macrophages in ALD. On the other hand, HSP90B1/GP96 induced preferably in liver macrophages promotes inflammation via glycolysis and its inhibition induces GRP78+ATF3+Trem2+ restorative/reparative macrophages resolving ALD. We hypothesize that alcohol induced HSP90AA1 facilitates macrophage aerobic glycolysis via epigenetic mechanisms whereas HSP90B1/GP96 and ER stress facilitate macrophage glycolysis via HIF1α in ALD. Inhibition of HSP90 in ALD induces ATF3+Trem2+ reparative macrophages using OXPHOS facilitating protection. The specific Aims of this proposal are - 1) To identify HSP90AA1 mediated epigenetic and metabolic programming of macrophages in murine ALD in vivo and human AH PBMCs in vitro. 2) To characterize the significance of macrophage-specific HSP90B1/GP96 in macrophage metabolism and assess significance of ATF3 and TREM2 in macrophages conferring protection from liver injury. Collectively, during the next project period our studies will identify novel metabolic and epigenetic mechanisms regulated by HSP90 and characterize reparative macrophages crucial in resolution of ALD. Studying these pathways in mouse ALD model and human AH patient monocytes will provide basis for future clinical development of HSP90 in ALD.

抽象的肝脏免疫细胞激活是酒精相关性肝病 (ALD) 的核心，但人们对此知之甚少。蛋白质稳态网络/途径对于保护细胞蛋白质组免受细胞应激至关重要。其中，蛋白质稳态介质 HSP90 作为治疗靶点被广泛研究和探索我们报道了 HSP90 的两种亚型：HSP90AA1（应激诱导型细胞质 HSP90）和 HSP90B1/GP96（HSP90 的内质网旁系同源物）在 ALD 中很重要。该项目最后资助期间的研究表明 HSP90 在 ALD 中的病理生理学作用。在 ALD 中使用纳米颗粒靶向 HSP90 抑制剂 17-DMAG 可以预防和逆转肝损伤，巨噬细胞中的 GP96/HSP90B1 缺陷促进肝脏炎症和 ALD、M-TLR4 缺陷的消退小鼠无法免受 ALD 的影响，抑制 HSP90 会降低 NLRP3 炎性体活性，从而降低 IL-1β 蛋白质和 HSF1 部分有助于减少促炎信号传导，而 HSF1 的缺乏则不会不能预防 ALD，表明 HSF1 在下一个项目期间不会有助于解决 ALD。我们将研究HSP90AA1和HSP90B1/GP96在酒精性肝病中介导的机制我们认为 HSP90 通过替代机制诱导炎症。（独立于 HSP90/TLR4 轴），例如通过表观遗传机制的巨噬细胞有氧糖酵解或在我们的初步数据中，我们发现 HSP90AA1 在 ALD 的细胞核中被检测到，并且它的抑制可以调节染色质修饰酶的表达试验数据还表明 HSP90AA1 的抑制作用。酒精会降低葡萄糖转运蛋白 (SLC2a1/GLUT1) 和己糖激酶 II 的介导诱导，这两个重要的酶糖酵解介质，表明 HSP90 在 ALD 中 M1 巨噬细胞的代谢编程中发挥作用。另一方面，HSP90B1/GP96 优选在肝脏巨噬细胞中诱导，通过糖酵解促进炎症其抑制作用可诱导 GRP78+ATF3+Trem2+ 恢复性/修复性巨噬细胞解决 ALD。酒精诱导的 HSP90AA1 通过表观遗传促进巨噬细胞有氧糖酵解 HSP90B1/GP96 和 ER 应激通过 HIF1α 在 ALD 中促进巨噬细胞糖酵解。使用 OXPHOS 促进 ALD 中 HSP90 的抑制诱导 ATF3+Trem2+ 修复性巨噬细胞该提案的具体目标是 - 1) 鉴定 HSP90AA1 介导的表观遗传和代谢。体内小鼠 ALD 和体外人 AH PBMC 中巨噬细胞的编程 2) 表征。巨噬细胞特异性 HSP90B1/GP96 在巨噬细胞代谢中的意义及其评估意义在下一个项目中，巨噬细胞中的 ATF3 和 TREM2 共同保护肝脏免受损伤。在此期间，我们的研究将确定由 HSP90 调节的新代谢和表观遗传机制，并表征修复性巨噬细胞对于 ALD 的解决至关重要，研究小鼠 ALD 模型和人类中的这些途径。 AH 患者单核细胞将为 HSP90 在 ALD 中的未来临床开发提供基础。