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Principal Investigator: Virender Kumar
Organization: UNIVERSITY OF TOLEDO
Fiscal Year: 2023
Award: $390,185
Funding agency: National Institute on Alcohol Abuse and Alcoholism
PROJECT SUMMARY
Alcohol-associated liver disease (ALD) is a significant health problem caused by excessive alcohol consumption.
ALD is generally discovered in association with fatty liver, steatosis, or fibrosis progression, leading to cirrhosis.
Unfortunately, there is no approved drug for ALD, and the current therapies rely on abstinence, immune
suppressants like corticosteroids, or liver transplantation in case of advanced cirrhosis. Studies suggest that
inflammation plays a significant role in ALD initiation and progression. Kupffer cells (KCs), the residing
macrophages in the liver, are mainly involved in hepatic inflammatory reactions. KCs, upon contact with injured
hepatocytes or gut bacterial endotoxins such as lipopolysaccharides (LPS), get activated and secrete
inflammatory cytokines, including TNF-α and start the inflammation. Pharmacological inhibition of KCs by small
molecules such as gadolinium chloride or decreasing intestinal bacterial load with antibiotics is shown to prevent
liver injury and ALD progression. Cyclic adenosine monophosphate (cAMP) signaling plays a significant role in
dampening hepatic injury and steatosis. Alcohol is known to increase the expression of cAMP degrading enzyme
phosphodiesterase 4 (PDE4). The upregulated PDE4 decreases the cAMP levels and induces liver
inflammation/injury. PDE4 inhibitors have been investigated to inhibit macrophage recruitment and activation in
ALD; however, the current PDE4 inhibitors such as rolipram and roflumilast are associated with severe side
effects, including nausea, vomiting, diarrhea, and dyspepsia. This study aims to inhibit PDE4B activity by novel
inhibitor KVA-D-88 in alcohol-induced steatosis. Our preliminary data show that KVA-D-88 is a potent and
selective PDE4B inhibitor with a suitable pharmacokinetic profile. The development of highly selective PDE4B
inhibitors such as KVA-D-88 directly applies to human ALD. However, PDE4B inhibition in other organs, such
as the brain, is known to produce severe side effects. Therefore, there is a need for KC-specific drug delivery to
enhance the drug efficacy and specificity. We will develop KVA-D-88 nanoparticles for liver-specific PDE4B
inhibition. Our specific aims are Aim 1 to establish the role of PDE4B inhibitor KVA-D-88 in ALD in vitro and
in vivo. In this aim, we will determine the specificity of KVA-D-88 to inhibit PDE4B isotype compared to PDE4D
isotype in alcohol-induced primary KCs, hepatocytes, and hepatic stellate cells (HSCs). Next, we will evaluate
the effect of KVA-D-88 mediated PDE4B inhibition on cAMP signaling, TNF-α induced ER stress, and ethanol-
induced toxicity in the modified NIAAA mouse model. Aim 2. Formulate and characterize KCs targeted KVA-
D-88 loaded polyethylene glycol (PEG) decorated solid lipid nanoparticles (SLNs). In this aim, we will
develop and characterize KCs targeted PEG-SLNs loaded with KVA-D-88. Next, we will evaluate the therapeutic
efficacy of KVA-D-88 loaded SLNs in the NIAAA model. This project is highly significant as it could provide us
with ALD therapy and a potential platform for nonalcoholic fatty liver disease (NAFLD) and cholestasis-induced
liver fibrosis.
Terms: <(TNF)-α><3'5'-cyclic ester of AMP><3,5 cyclic AMP synthetase><Abdominal Pain><Absolute ethanol><Abstinence><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adenyl Cyclase><Adenylate Cyclase><Adenylyl Cyclase><Adrenal Cortex Hormones><Adverse effects><Alcohol Chemical Class><Alcohol Drinking><Alcohol consumption><Alcoholic><Alcoholic Liver Diseases><Alcohols><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antiinflammatory Effect><BBB crossing><Bile Duct Obstruction><Biliary Stasis><Binding><Blood monocyte><Body Tissues><Boozer><Brain><Brain Nervous System><Cachectin><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cholestasis><Cicatrix><Circulation><Cirrhosis><Corticoids><Corticosteroids><Cyclic AMP><Cyclic AMP-Dependent Protein Kinases><Cyclic GMP><Cyclic Nucleotides><Data><Dendritic Cells><Dependent drinker><Deposit><Deposition><Development><Diarrhea><Diet><Disease Progression><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drugs><Dyspepsia><ER stress><ETOH><Emesis><Encephalon><Endoplasmic Reticulum><Endotoxins><Enzyme Gene><Enzymes><Ergastoplasm><EtOH drinking><EtOH use><Ethanol><Ethanol Metabolism><Ethyl Alcohol><Fats><Fatty Liver><Fatty acid glycerol esters><Fibrosis><Gene Transcription><Generations><Genetic Transcription><Grain Alcohol><Guanosine Cyclic Monophosphate><Gut Epithelial Permeability><Gut Hyperpermeability><Gut permeability><Health><Heavy Drinking><Hepatic><Hepatic Cells><Hepatic Cirrhosis><Hepatic Disorder><Hepatic Failure><Hepatic Parenchymal Cell><Hepatic Stellate Cell><Hepatic Transplantation><Hepatocyte><Histology><Homolog of Drosophila TOLL><Human><Hydrophobicity><Immune><Immunes><Immunoglobulin Enhancer-Binding Protein><In Vitro><Indigestion><Inflammation><Inflammatory><Inflammatory Response><Injury><Injury to Liver><Intestinal><Intestinal Epithelial Permeability><Intestinal Hyperpermeability><Intestinal permeability><Intestines><Intracellular Communication and Signaling><Intracellular Second Messenger><Ito Cell><Kupffer Cells><Lipopolysaccharides><Liver><Liver Cells><Liver Cirrhosis><Liver Failure><Liver Fibrosis><Liver Grafting><Liver Steatosis><Liver Transplant><Liver diseases><Macrogols><Macrophage><Macrophage-Derived TNF><Marrow monocyte><Mediating><Medication><Methylcarbinol><Mice><Mice Mammals><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular Interaction><Monocyte-Derived TNF><Morbidity><Morbidity - disease rate><Murine><Mus><Mφ><NADH><NAFLD><NF-kB><NF-kappa B><NF-kappaB><NFKB><NIAAA><National Institute on Alcohol Abuse and Alcoholism><Nausea><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Organ><PDE4 enzyme><PDE4B><PDase IV><PKA><Permeability><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Phosphodiesterases><Play><Polyethylene Glycols><Polyethylene Oxide><Polyethyleneoxide><Polyoxyethylenes><Process><Production><Protein Kinase A><RNA Expression><Reaction><Role><Rolipram><Scars><Second Messenger Systems><Second Messengers><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Specificity><Stellate Sinusoidal Macrophage><Superoxide Anion><Superoxide Radical><Superoxides><TLR protein><TLR4><TLR4 gene><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Tissues><Toll Homologue><Toll-Like Receptor Family Gene><Toll-like receptors><Toxic effect><Toxicities><Transcription><Transcription Factor NF-kB><Treatment Efficacy><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><United States><Veiled Cells><Vomiting><adenosine 3'5' monophosphate><adenylcyclase><alcohol effect><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol ingestion><alcohol intake><alcohol metabolism><alcohol prevention><alcohol product use><alcohol related liver disease><alcohol use><alcohol-associated liver disease><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic beverage consumption><alcoholic drink intake><alcoholic liver injury><antagonism><antagonist><anti-inflammatory effect><bacteria in the gut><bile obstruction><bile occlusion><biological signal transduction><blood-brain barrier crossing><bloodbrain barrier crossing><bowel><cAMP><cAMP-Dependent Protein Kinases><cGMP><cholestatic diseases><cholestatic disorder><cholestatic liver disease><cholestatic liver disorder><cholestatic syndromes><cirrhotic><cytokine><developmental><diets><drink heavily><drug efficacy><drug/agent><endoplasmic reticulum stress><ethanol consumption><ethanol drinking><ethanol effect><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol ingestion><ethanol intake><ethanol liver disease><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><excessive alcohol consumption><excessive alcohol ingestion><excessive alcohol intake><excessive drinking><excessive ethanol ingestion><extreme drinking><fibrotic liver><gadolinium chloride><gastrointestinal><gut bacteria><heavy alcohol use><hepatic body system><hepatic damage><hepatic disease><hepatic fibrosis><hepatic inflammation><hepatic injury><hepatic organ system><hepatic steatosis><hepatocyte injury><hepatopathy><hepatosteatosis><improved><in vivo><inflamed liver><inhibitor><injuries><intervention efficacy><kappa B Enhancer Binding Protein><lipid based nanoparticle><lipid nanoparticle><liver damage><liver disorder><liver inflammation><liver injury><liver macrophage><liver transplantation><monocyte><mortality><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><non-alcohol fatty liver disease><non-alcoholic fatty liver disease><non-alcoholic liver disease><nonalcoholic fatty liver disease><novel><nuclear factor kappa beta><oxidative damage><oxidative injury><pharmacologic><phosphodiesterase 4><phosphodiesterase 4B><phosphodiesterase 6><phosphodiesterase IV><phosphodiesterase type 6><phosphoric diester hydrolase><prevent><prevent alcohol><preventing><preventing alcohol><problem drinker><recruit><retinal phosphodiesterase 6><side effect><signal transduction second messengers><small molecule><social role><therapeutic efficacy><therapeutic evaluation><therapeutic target><therapeutic testing><therapy efficacy><toll-like receptor 4><type 4 cyclic nucleotide phosphodiesterase>