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Principal Investigator: SUBHASH C. PANDEY
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2024
Award: $1,654,361
Funding agency: National Institute on Alcohol Abuse and Alcoholism
Project Summary:
Alcohol use disorder (AUD) can be characterized by a pattern of compulsive alcohol drinking or loss of control
over alcohol drinking. The positive and negative effects of ethanol appear to be regulated by genetic and
epigenetic changes in several key brain regions. Long-term alcohol use causes structural and functional
changes in the prefrontal cortex (PFC), hippocampus, amygdala, and ventral tegmental area of the brain which
may drive behavioral phenotypes, such as anxiety, depression, motivation, and increased alcohol drinking.
Several protein families such as histone deacetylases (HDACs), histone acetyltransferases (HATs), histone
methyltransferases (HMTs), DNA methyltransferases (DNMTs), lysine demethylases, and DNA demethylases
are important players in chromatin remodeling within the genome and are altered by chronic ethanol exposure
and withdrawal. However, the interplay between these different epigenetic modifiers lead to an altered state of
the epigenome and their role in transcriptomic changes associated with adaptations in the reward and stress
systems in the brain (VTA, amygdala, PFC, and hippocampus) during AUD is still unclear. The overall aim of
this Alcohol Research Center is to evaluate the epigenetic and genetic basis of molecular changes in
the brain that underlie behavioral changes in AUD. This P50 application entitled “Center for Alcohol
Research in Epigenetics (CARE)” consists of four highly inter-related preclinical and translational research
projects [research project #1, VTA, (Brodie /Glover), research project #2, Amygdala, (Pandey), research project
#3, Hippocampus, (Lasek) and research project #4, PFC, (Guidotti/Grayson/Gavin)] and two current pilot
projects [pilot project #1 (Epigenetic biomarkers in AUD), and pilot project #2 (Epitranscriptomic modifications in
AUD)], and three Cores [Administrative (Pandey/Lasek), Epigenetics (Grayson/Maienschein-Cline), and
Behavioral Core (Glover/Zhang)]. In addition, the CARE will serve as an important resource and provide a
scientifically enriched environment for training opportunities for the next generation of neuroscientists studying
AUD and will disseminate scientific knowledge of AUD to the general public through a community outreach
program. The primary thematic focus of CARE, as a whole, will be to mechanistically link emerging novel
molecular targets identified by whole-genome approaches (ATAC-seq, ChIP-seq, RNA-seq, and DNA
methylation/demethylation EPIC array) in the proposed brain circuitry to behavioral phenotypes. Mechanistic
approaches (CRISPR-dCas9, shRNA, siRNA, chemogenetic) will be used to manipulate the epigenome
through alterations of either histone acetylation/methylation mechanisms or DNA methylation mechanisms, in
key brain circuitry that regulates behavioral phenotypes associated with AUD (anxiety, depression, motivation,
and alcohol drinking) in order to better understand the pathophysiology of AUD and develop better
pharmacotherapy.
Terms: <ATAC sequencing><ATAC-seq><ATACseq><Aberrant DNA Methylation><Alcohol Drinking><Alcohol consumption><Alcohol dependence><Alcohol withdrawal syndrome><Alcoholic><Alcoholism><Ammon Horn><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Anatomic Sites><Anatomic structures><Anatomy><Animal Model><Animal Models and Related Studies><Animals><Anxiety><Area><Assay for Transposase-Accessible Chromatin using sequencing><Autopsy><Behavioral><Bio-Informatics><Bioinformatics><Boozer><Brain><Brain Nervous System><Brain region><CRISPR><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><ChIP Sequencing><ChIP-seq><ChIPseq><Characteristics><Chemicals><Chromatin><Chromatin Structure><Chronic><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Common Rat Strains><Communities><Community Outreach><Cornu Ammonis><DNA><DNA Methylation><DNA Methyltransferase><DNA Modification><DNA Modification Methylases><DNA Modification Methyltransferases><DNA Modification Process><DNA Molecular Biology><DNA-Methyltransferases><Data><Data Analyses><Data Analysis><Deoxyribonucleic Acid><Dependence><Dependent drinker><Development><Differential Gene Expression><Disease><Disorder><Dnmt><Drug Therapy><Dysfunction><Electrophysiology><Electrophysiology (science)><Emotional><Encephalon><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><EtOH drinking><EtOH use><Expression Signature><Functional disorder><Funding><Gene Action Regulation><Gene Expression><Gene Expression Profile><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><General Population><General Public><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genome><Glucocorticoid Receptor><HDAC><HDAC Proteins><HPA axis><High School Student><Hippocampus><Histone Acetylase><Histone Acetylation><Histone Deacetylase><Histones><Human><Intake><Intracellular Communication and Signaling><Investigation><Investigators><Knowledge><L-Lysine><Lead><Link><Lysine><MD students><Maintenance><Mediating><Medical Students><Mental Depression><Methylation><Modern Man><Modification><Modification Methylases><Molecular><Molecular Biology><Molecular Target><Motivation><Mutation><Nerve Transmitter Substances><Network Analysis><Neuroimmune><Neuropeptides><Neurophysiology - biologic function><Neurophysiology / Electrophysiology><Neurosciences><Neurotransmitters><Non-Polyadenylated RNA><Pathogenesis><Pathway Analysis><Pathway interactions><Pattern><Pb element><Pharmacotherapy><Physiopathology><Pilot Projects><Play><Postdoc><Postdoctoral Fellow><Prefrontal Cortex><Protein Family><Psychiatry><Public Health><R-Series Research Projects><R01 Mechanism><R01 Program><RNA><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><Rat><Rats Mammals><Rattus><Regulation><Research><Research Associate><Research Grants><Research Personnel><Research Project Grants><Research Projects><Research Resources><Researchers><Resources><Rewards><Ribonucleic Acid><Rodent Model><Role><Scientist><Secondary School Student><Secondary Student><Self Administered><Self Administration><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Site-Specific DNA-methyltransferase><Small Interfering RNA><Stress><Synapses><Synaptic><System><Testing><Time><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Translational Research><Translational Science><Ventral Tegmental Area><Visit><Withdrawal><addiction><addictive disorder><alcohol addiction><alcohol dependency><alcohol dependent><alcohol effect><alcohol exposed><alcohol exposure><alcohol ingestion><alcohol intake><alcohol product use><alcohol related research><alcohol research><alcohol use><alcohol use disorder><alcohol use prevention><alcohol withdrawal><alcoholic beverage consumption><alcoholic drink intake><amygdaloid nuclear complex><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><behavior phenotype><behavioral phenotyping><biological signal transduction><brain circuitry><chromatin immunoprecipitation-sequencing><chromatin remodeling><data interpretation><demethylation><depression><deter alcohol use><developmental><drinking><drug treatment><electrophysiological><entire genome><environment enrichment><environment enrichment for laboratory animals><environmental enrichment><environmental enrichment for laboratory animals><epigenetic biomarker><epigenetic marker><epigenetically><epigenome><epitranscriptome><epitranscriptomics><ethanol consumption><ethanol drinking><ethanol effect><ethanol exposed><ethanol exposure><ethanol ingestion><ethanol intake><ethanol product use><ethanol research><ethanol use><ethanol use disorder><ethanol withdrawal><exposed to alcohol><exposed to ethanol><exposure to alcohol><exposure to ethanol><full genome><gene expression pattern><gene expression signature><gene network><genetic approach><genetic strategy><genome mutation><genome scale><genome-wide><genomewide><global gene expression><global transcription profile><graduate student><heavy metal Pb><heavy metal lead><high schoolers><higher education><hippocampal><histone H3 methyltransferase><histone acetyltransferase><histone methylase><histone methyltransferase><histone modification><hypothalamic-pituitary-adrenal (HPA) axis><hypothalamic-pituitary-adrenal axis><hypothalmus-pituitary-adrenal axis><interdisciplinary approach><medical school students><model of animal><molecular phenotype><multidisciplinary approach><necropsy><neural adaptation><neural function><neuroactive steroids><neuroadaptation><neurosteroids><neurotrophic factor><neurotrophin><neutrophin><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><next generation><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><outreach program><pathophysiology><pathway><pilot study><post-doc><post-doctoral><post-doctoral trainee><postmortem><pre-clinical research><preclinical research><prevent alcohol use><problem drinker><research associates><shRNA><short hairpin RNA><siRNA><small hairpin RNA><social role><synapse><training opportunity><transcriptional profile><transcriptional signature><transcriptome><transcriptome sequencing><transcriptomic sequencing><transcriptomics><translation research><translational investigation><undergrad><undergraduate><undergraduate student><ventral tegmentum><viral gene delivery><whole genome><withdrawal from alcohol>