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Principal Investigator: Irina A. Kirpich
Organization: UNIVERSITY OF LOUISVILLE
Fiscal Year: 2022
Award: $264,780
Funding agency: National Institute on Alcohol Abuse and Alcoholism
Alcoholic liver disease (ALD) is a major and increasing health problem in the US (especially in Kentucky) and
worldwide. In spite of the magnitude of this problem, there is no FDA-approved therapy for any stage of ALD. In
addition, the mechanisms and regulators of the disease progression and severity are not well understood. Dietary
fats play an important interactive role with alcohol consumption in ALD pathogenesis, however, the role of n3
PUFAs in ALD are not well defined. Our central hypothesis is that n3 PUFAs are beneficial in ALD, in part, via
n3-PUFA-derived pro-resolving mediators which facilitate inflammation resolution, improvement in the gut-liver
axis, and subsequent attenuation of liver injury. We propose that resolvin D1 (RvD1) is a potent therapeutic
agent in severe ALD acting via RvD1-FPR2-NEAT1 signaling to suppress pro-inflammatory cytokines and to
promote repair of hepatocellular damage, in part, via enhancement of pro-restorative macrophages. We
postulate that compromised inflammation resolution due to impaired RvD1 production/signaling is one of the
critical nutritional contributing factors to the progressive ALD and severity of alcoholic hepatitis (AH) in humans.
The Specific Aims of the proposal are: Aim 1. To test whether n3 PUFAs exert beneficial effects on EtOH-
associated liver injury/inflammation by enhancing the effectiveness of inflammation resolution and by
repair of hepatocellular damage through increase in n3-PUFA-derived specialized pro-resolving mediators
promoting
(SPMs), and RvD1-FPR2 and Neat1-mediated suppression of pro-inflammatory cytokine signaling and
reprogramming pro-inflammatory macrophages into a pro-restorative phenotype. Wild Type (WT), Fpr2-/-,
Neat1-/-, and transgenic fat-1 mice (which are able to endogenously convert n6 to n3 PUFAs) will be used in this
Aim. We will also examine the therapeutic effectiveness of RvD1 utilizing a novel nanoparticle technology of
targeted RvD1 delivery examine the role n3-PUFAs
to the liver with plant-derived edible exosomes. Aim 2. To
and RvD1 in maintaining gut barrier integrity, and in the resolution of intestinal inflammation in experimental ALD.
We will: i) test in vivo, in animal models, and in vitro, in intestinal organoid culture, whether n3 PUFA or RvD1
improve intestinal barrier damage by attenuating intestinal immune dysregulation; ii) test in vivo whether
disruption of the RvD1-FPR2 axis exacerbates, while blocking Neat1 signaling attenuates intestinal inflammation
and alterations in the gut barrier integrity; iii) test a novel therapeutic strategy of administering an engineered
bacteria strain to convert n6 to n3 PUFAs in the intestine and thus to attenuate gut barrier dysfunction in mice.
In Aim 3, we seek to translate and extend our findings in animal models to human ALD. Utilizing de-identified
human samples we will: i) determine effects of n3-PUFA dietary supplementation on plasma SPM levels, markers
of liver injury, systemic inflammation, and intestinal permeability in heavy drinking individuals; ii) examine plasma
SPM levels, and SPM synthesis in whole blood and peripheral blood monocytes (PBMCs) obtained from AH
patients; and iii) test whether RvD1 improves phagocytosis/efferocytosis of PBMCs obtained from AH patients.
Terms: <ALXR><Absolute ethanol><Alcohol Chemical Class><Alcohol Drinking><Alcohol consumption><Alcoholic Hepatitis><Alcoholic Liver Diseases><Alcohols><Animal Model><Animal Models and Related Studies><Attenuated><Autoregulation><Bacteria><Biological Response Modifiers><Biomodulators><Blood Plasma><Blood monocyte><Body Tissues><Cell Communication and Signaling><Cell Signaling><Chronic><Cytokine Signal Transduction><Cytokine Signaling><Data><Development><Diet><Dietary Fats><Dietary Fatty Acid><Dietary Supplementation><Disease Progression><Down-Regulation><Downregulation><Dysfunction><ETOH><Effectiveness><Engineering><EtOH drinking><EtOH use><Ethanol><Ethanol-induced hepatitis><Ethyl Alcohol><Experimental Animal Model><FDA approved><FPR2><FPR2 gene><FPRH1><FPRL1><Fats><Fatty acid glycerol esters><Formyl Peptide Receptor 2><Formyl Peptide Receptor Homolog 1><Formyl Peptide Receptor-Like 1><Functional disorder><Grain Alcohol><Gut Epithelial Permeability><Gut Hyperpermeability><Gut permeability><HM63><Health><Heavy Drinking><Hepatic><Hepatocellular Damage><Homeostasis><Host Defense><Human><Immune><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immune response><Immunes><Immunological response><Impairment><In Vitro><Individual><Inflammation><Inflammatory><Injury to Liver><Intestinal><Intestinal Epithelial Permeability><Intestinal Hyperpermeability><Intestinal permeability><Intestines><Intracellular Communication and Signaling><Kentucky><LXA4R><Linoleic Acids><Lipoxin A4 Receptor><Liver><Marrow monocyte><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Methylcarbinol><Mice><Mice Mammals><Microbe><Modeling><Modern Man><Molecular><Murine><Mus><Mφ><Nuclear><Nutritional><Organoids><Pathogenesis><Patients><Phagocytosis><Phenotype><Physiological Homeostasis><Physiopathology><Plants><Plasma><Plasma Serum><Play><Production><Prognosis><Receptor Protein><Research><Resolution><Reticuloendothelial System, Serum, Plasma><Rodent><Rodentia><Rodents Mammals><Role><Sampling><Severities><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Survivors><Technology><Testing><Therapeutic Agents><Tissues><Transcript><Transgenic Organisms><Translating><Whole Blood><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><alcohol-related liver disease><alcoholic beverage consumption><alcoholic drink intake><alcoholic liver injury><attenuation><base><biological signal transduction><bowel><bowel inflammation><cytokine><developmental><diet supplementation><dietary lipid><diets><disease severity><drink heavily><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><excessive alcohol consumption><excessive alcohol ingestion><excessive alcohol intake><excessive drinking><excessive ethanol ingestion><exosome><extreme drinking><gut inflammation><gut-liver axis><heavy alcohol use><hepatic body system><hepatic damage><hepatic inflammation><hepatic injury><hepatic organ system><host response><immune system response><immunomodulatory biologics><immunoresponse><improved><in vivo evaluation><in vivo testing><inflamed bowel><inflamed gut><inflamed intestine><inflamed liver><injury to organs><intestinal barrier><intestinal inflammation><intestinal mucosal barrier><lipid mediator><liver damage><liver inflammation><liver injury><macrophage><model of animal><model organism><monocyte><nano particle><nano-sized particle><nanoparticle><nanosized particle><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><nutrition><nutritious><organ injury><pathophysiology><peripheral blood><pre-clinical study><preclinical study><receptor><repair><repaired><social role><systemic inflammation><systemic inflammatory response><therapeutic effectiveness><tissue repair><transgenic>