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Principal Investigator: Pranoti Mandrekar
Organization: UNIV OF MASSACHUSETTS MED SCH WORCESTER
Fiscal Year: 2019
Award: $376,875
Funding agency: National Institute on Alcohol Abuse and Alcoholism
DESCRIPTION (provided by applicant): Activation of liver resident macrophages and increased pro-inflammatory cytokine production is a hallmark in the pathogenesis of alcoholic liver disease (ALD). Alcohol-induced oxidative stress plays an important role in macrophage activation. Stress induced heat shock proteins (hsps) function as molecular chaperones of signaling molecules important in macrophage activation. Heat shock protein 90 (hsp90) and its ER form, Grp94/gp96 are crucial chaperones of signaling molecules in the TLR4 pathway and thus regulate inflammatory cytokines. Together, hsp90 and gp96 can link stress and inflammatory pathways and play an important role in development of ALD. Studies during the last funding period of this project established that: 1) hsp90α (cytoplasmic) and gp96/grp94 (endoplasmic reticulum (ER) form of hsp90), but not hsp70 is increased in hepatic macrophages and whole livers of chronic alcohol-fed mice and in human alcoholic hepatitis livers, 2)Hsp90α chaperones IKKβ and IRF3 and facilitates TLR4 signaling 2) Inhibition of hsp90 in vivo using pharmacological agent 17-DMAG protects mice from alcoholic liver injury, 3) Myeloid-specific gp96 deficiency alleviates alcoholic liver injury 4) HSF1, although activated by alcohol is not sufficient for induction of hsp90α. On the other hand, HSF1 and hsp70 induced by hsp90 inhibitors during decreased injury is crucial for reduction of liver inflammatory responses. Here we hypothesize that cytoplasmic hsp90α and ER gp96/grp94 contribute to hepatic macrophage activation and are plausible therapeutic targets in ALD. Increased hsp90α promotes macrophage activation and gp96 (unfolded protein response (UPR) gene) induced toll-like receptor 4 surface expression and hyperresponsiveness contributes to macrophage sensitization in alcoholic liver disease. Finally we propose that HSF1 and hsp70 exert anti-inflammatory effects during hsp90 inhibition in ALD. Use of hsp90 inhibitors will help unravel innovative pathways of cross-talk between stress proteins and inflammatory responses and establish hsp90 as a new therapeutic target in ALD. The Specific Aims are as follows: 1) To study the effect of hsp90α inhibition on macrophage activation in ALD by: A) Using hsp90α siRNA to target liver macrophages and 17-DMAG packaged nanoparticles in ALD. B) Examining the effect of hsp90α inhibition on macrophage polarization in the liver. C) Analysis of paracrine effect of macrophage specific hsp90α inhibition on alcoholic steatosis. 2) To investigate the function of myeloid gp96, ER paralog of hsp90, in alcohol-induced sensitization of macrophages by: A) Determine the regulation of gp96 expression during alcoholic liver injury. B) Study importance of gp96/TLR4 interaction and TLR4 hyperresponsiveness during ALD. C) Characterize the role of gp96 in macrophage UPR activation during ALD. 3) To assess anti-inflammatory effects of HSF1 and hsp70 during hsp90 inhibition in ALD: A) Evaluate the role of myeloid-specific HSF1 in macrophage activation and ALD. B) Investigate the role of HSF1 during 17-DMAG treatment and inhibition of ALD. C) Determine the role of hsp70, in anti-inflammatory responses during 17- DMAG treatment.
Terms: <Affect><Alcohol Chemical Class><Alcohol Drinking><Alcohol consumption><Alcoholic><Alcoholic Hepatitis><Alcoholic Liver Diseases><Alcohols><Anti-inflammatory><Antiinflammatory Effect><Basal Transcription Factor><Basal transcription factor genes><Boozer><Cancers><Cell Communication and Signaling><Cell Signaling><Cellular injury><Chaperone><Chronic><Cirrhosis><Clinical><Dependent drinker><Development><Disease><Disorder><Drug Delivery><Drug Delivery Systems><Drug Targeting><Endoplasmic Reticulum><Endotoxins><Ergastoplasm><EtOH drinking><EtOH use><Ethanol-induced hepatitis><Fatty Liver><Funding><General Transcription Factor Gene><General Transcription Factors><Genes><HSF1><HSP 90 inhibition><HSP-90><HSP90><HSP90 inhibition><Heat Stress><Heat Stress Disorders><Heat Stress Syndromes><Heat shock proteins><Heat-Shock Proteins 90><Hepatic><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><Homolog of Drosophila TOLL><Human><IFN-regulatory factor 3><IRF-3 protein><IRF3><IRF3 gene><Immune Cell Activation><Inflammation><Inflammatory><Inflammatory Response><Injury><Injury to Liver><Interferon Regulatory Factor 3><Intracellular Communication and Signaling><Kupffer Cells><Link><Liver><Liver Cells><Liver Cells Carcinoma><Liver Steatosis><Macrophage Activation><Malignant Neoplasms><Malignant Tumor><Mediating><Mice><Mice Mammals><Modern Man><Molecular Chaperones><Morbidity><Morbidity - disease rate><Murine><Mus><Myelogenous><Myeloid><Oxidative Stress><Pathogenesis><Pathway interactions><Pharmacology><Play><Primary carcinoma of the liver cells><Production><Property><Proteins><Regulation><Reporting><Resolution><Role><Short interfering RNA><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Small Interfering RNA><Steatohepatitis><Stellate Sinusoidal Macrophage><Stimulus><Stress><Surface><TLR4><TLR4 gene><Toll Homologue><Transcription Factor Proto-Oncogene><Transcription factor genes><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol ingestion><alcohol intake><alcohol product use><alcohol use><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcoholic beverage consumption><alcoholic drink intake><alcoholic liver injury><anti-inflammatory effect><antiinflammatory><base><biological adaptation to stress><biological signal transduction><cell damage><cell injury><cirrhotic><cytokine><developmental><ethanol consumption><ethanol drinking><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol ingestion><ethanol intake><ethanol product use><ethanol use><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><fat metabolism><global health><heat shock protein 90 inhibition><heat-related illness><hepatic body system><hepatic damage><hepatic injury><hepatic organ system><hepatic steatosis><hsp90 Family><in vivo><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><lipid metabolism><liver carcinoma><liver damage><liver injury><liver macrophage><macrophage><malignancy><mortality><nano emulsion><nano particle><nano-sized particle><nanoemulsion><nanoparticle><nanosized particle><neoplasm/cancer><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><paracrine><paralog><paralogous gene><pathway><pre-clinical><preclinical><problem drinker><public health relevance><reaction; crisis><response><siRNA><siRNA therapy><siRNA-based therapeutic><social role><stress protein><stress response><stress; reaction><therapeutic siRNA><therapeutic target><toll-like receptor 4><transcription factor>