权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要