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Principal Investigator: Ilhem Messaoudi
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2019
Award: $173,809
Funding agency: National Institute on Alcohol Abuse and Alcoholism
Alcohol use disorder (AUD) contributes significantly to disease burden and mortality in the United States, with
an annual healthcare cost of $223 billion and a death toll of nearly 88,000. Current methods to assess alcohol
intake rely primarily on self-report surveys or biochemical measures of liver injury. However, these methods
are rather insensitive and unreliable since subjects are often not forthcoming and liver injury is not the only
indication of ethanol-mediated organ damage, which includes increased incidence of gastrointestinal cancers
and exacerbation of diabetes and cardiovascular disease. Moreover, alcohol consumption affects human
health in a dose-dependent manner; light to moderate drinkers have a lower risk of all-cause mortality than
abstainers while heavy drinkers are at the highest risk. Similarly, alcohol consumption modulates immunity in a
dose-dependent manner. Specifically, AUD results in poor response to vaccination, enhanced susceptibility to
infection, and poor wound healing, whereas moderate ethanol consumption leads to improved vaccine
responses. Therefore, there is an urgent need to develop sensitive, robust, non-invasive markers of ethanol
consumption. Extracellular RNA (exRNA) serves as efficient biomarkers of cancer, cardiovascular risk, liver
injury and placental dysfunction. These exRNA circulate either packaged within exosomes, or bound to
lipoproteins or other proteins, making them very stable. Given the role cellular miRNAs play in regulating gene
expression following alcohol exposure, their potential to provide reliable biomarkers of ethanol consumption is
high. However, our current understanding of alcohol-induced changes in exRNA is limited to a few exosome-
bound microRNAs, which are increased in circulation in alcoholic liver disease models or after in vitro
treatment of monocytes with rather high doses of ethanol. Thus, there is a crucial need to uncover additional
dose-sensitive exosome-bound miRNA as well as identify miRNA cargo bound to protein and lipoproteins. In
this application, we will address this critical gap in knowledge by first identifying ethanol-mediated changes in
extracellular microRNA (ex-miRNA) bound to exosomes, lipoproteins, and proteins by leveraging a robust
nonhuman primate model of voluntary chronic (12 months) ethanol self-administration in combination with a
novel RNA-Differential Isolation Platform (RNA-DIP) and next generation sequencing. Additionally, we will test
the functional impact of over-represented miRNA packaged in exosomes and delivered into monocytes from
ethanol naïve animals. We will assess the downstream effect of miRNA uptake by stimulating the cells with
lipopolysaccharide (LPS) and measuring both changes in transcription and protein levels of inflammatory
mediators. These experiments will be carried out in collaboration with Dr. Grant who developed the voluntary
ethanol self-administration model, Dr. Zhong who developed the RNA-DIP chip to simultaneously isolate all
three exRNA fractions, and Dr. Zhao who bears expertise in manipulating stem cell behavior by delivering
exosome-bound miRNA. Completion of the studies proposed in this application will yield unprecedented insight
into ethanol dose-dependent alterations in exRNA cargo, their potential role as biomarkers of ethanol
consumption, and their impact on inflammation.
Terms: <Absolute ethanol><Address><Adverse effects><Affect><Alcohol Chemical Class><Alcohol Drinking><Alcohol consumption><Alcoholic Hepatitis><Alcoholic Liver Diseases><Alcoholic beverage heavy drinker><Alcohols><Animals><Bears><Binding Proteins><Biochemical><Biological><Biological Markers><Blood Circulation><Blood Plasma><Blood monocyte><Bloodstream><Breast Cancer Patient><Breast Tumor Patient><Cardiovascular Diseases><Cell Body><Cell Line><CellLine><Cells><Cessation of life><Chemistry><Chronic><Circulation><Cognitive Discrimination><Collaborations><Communication><Consumption><Coupled><Data><Death><Diabetes Mellitus><Diagnostic><Differentation Markers><Differentiation Antigens><Differentiation Markers><Discrimination><Disease><Disease model><Disorder><Dose><Dysfunction><ETOH><Ensure><EtOH drinking><EtOH use><Ethanol><Ethanol dependence><Ethanol-induced hepatitis><Ethyl Alcohol><Frequencies><Functional disorder><Future><GI cancers><GI malignancies><GI tract cancers><Gastrointestinal Cancer><Gastrointestinal Tract Cancer><Gene Expression><Gene Targeting><Gene Transcription><Genetic Transcription><Global Change><Grain Alcohol><Grant><Health><Health Care Costs><Health Costs><Healthcare Costs><Heavy Drinker><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Human><Immune><Immune response><Immunes><Immunity><Immunological response><Immunomodulation><In Vitro><Incidence><Infection><Inflammation><Inflammation Mediators><Inflammatory><Inflammatory Response><Injury to Liver><Knowledge><Laboratories><Ligand Binding Protein><Ligand Binding Protein Gene><Light><Lipopolysaccharides><Lipoproteins><Liver Cells><Macaca><Macaque><Malignant Gastrointestinal Neoplasm><Malignant neoplasm of gastrointestinal tract><Marker Antigens><Marrow monocyte><Measures><Mediating><Messenger RNA><Methods><Methylcarbinol><Micro RNA><MicroRNAs><Modeling><Modern Man><Morbidity><Morbidity - disease rate><NGS Method><NGS system><Neurosciences><Non-Polyadenylated RNA><Organ><Outcome><PBMC><Pathway interactions><Patient Self-Report><Peripheral Blood Mononuclear Cell><Photoradiation><Physiopathology><Plasma><Plasma Serum><Play><Predisposition><Production><Progenitor Cells><Protein Binding><Proteins><RNA><RNA Expression><RNA Gene Products><Regulation><Reporting><Resolution><Reticuloendothelial System, Serum, Plasma><Ribonucleic Acid><Risk><Rodent Model><Role><Sampling><Self Administration><Self-Administered><Self-Report><Small RNA><Stem Cell Research><Stem cells><Strains Cell Lines><Survey Instrument><Surveys><Susceptibility><Testing><Transcription><United States><Up-Regulation><Upregulation><Ursidae><Ursidae Family><Vaccination><Wound Healing><Wound Repair><alcohol effect><alcohol exposed><alcohol exposure><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol ingestion><alcohol intake><alcohol product use><alcohol use><alcohol use disorder><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><bear><bio-markers><biologic marker><biomarker><bound protein><burden of disease><burden of illness><cancer biomarkers><cancer markers><cardiovascular disorder><cardiovascular risk><cardiovascular risk factor><cell behavior><cellular behavior><circulating biomarkers><circulating markers><cultured cell line><cytokine><diabetes><disease burden><disorder model><ethanol addiction><ethanol consumption><ethanol dependency><ethanol drinking><ethanol effect><ethanol exposed><ethanol exposure><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol ingestion><ethanol intake><ethanol product use><ethanol use><ethanol use disorder><ethanol-dependent><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><exosome><experiment><experimental research><experimental study><exposed to alcohol><exposed to ethanol><exposure to alcohol><exposure to ethanol><extracellular><gastrointestinal malignancies><hepatic damage><hepatic injury><high risk><host response><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><inflammatory mediator><insight><liver damage><liver injury><mRNA><macrophage><miRNA><miRNA biomarkers><miRNA markers><miRNAs><microRNA biomarkers><microRNA markers><monocyte><mortality><next gen sequencing><next generation sequencing><nextgen sequencing><non-human primate><nonhuman primate><novel><pathophysiology><pathway><protein biomarkers><protein markers><response><social role><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><uptake><vaccine response><years of life lost to disability><years of life lost to disease>