EtOH-induced Immunomodulation: Role of Histone Deacetylases and Cannabinoid Genes Grant

abstract

  • PROJECT SUMMARY/ABSTRACT:The primary goal of this mentored career development K99 phase is to develop the knowledge, skills andexperience required to progress to an independent investigator R00 phase. The proposed career developmentplan includes the participation in seminars and scientific meetings to gain knowledge on the current alcoholaddiction research, improving laboratory research skills, and mentored learning to ensure a successfultransition to independence. This will create a solid platform of knowledge and skills. The mentored proposalunder the mentorship of Dr. Madhavan Nair will encourage hypothesis driven research and independentinvestigation. In the United States, 18 million Americans suffer from alcohol use disorders (AUD). Only 7.1% ofthese individuals received any treatment in the past year; and alcohol abuse (AA) contributes to 5% of deathannually. AA can contribute to a higher risk of infectious diseases and other undesirable medical conditionsinvolving complex interactions between the direct effects of alcohol and its toxic metabolites on variousimmune cells, induction of oxidative stress, and upregulation of the inflammatory cascade and inflammation-related genes such as cannabinoid genes (CBRs) and histone deacetylases (HDACs). The proposed work isrelevant to the mission and research interests of NIAAA since it will elucidate mechanisms underlying thebiomedical effects of alcohol in human immune cells and also combines alcohol with innovative research areasincluding CBRs and epigenetics. The proposed research that leads to the independent R00 phase of the awardis aimed to dissect the role of alcohol-associated epigenetic mechanisms in immune modulation of cannabinoidgenes. In recent years, chromatin remodeling has emerged as an important regulatory mechanism for drugaddiction and also in development of neurodegenerative disorders. Further, HDAC inhibitors (HDACi) havebeen known to modulate genes involved in drug addiction such as the ? opioid receptor gene (MOR), anddecrease cocaine self administration. However, the role HDACs play in AUDs has not been elucidated yet,particularly their ability to modulate drug and alcohol addiction associated genes in human dendritic cells.Accordingly, we hypothesize that alcohol modulates CBRs expressed in human monocyte-deriveddendritic cells (MDDCs), and the mechanisms may be mediated by HDACs and oxidative stress. Thespecific goals are to determine: 1. the levels of HDAC2, CB2, and GPR55 in MDDCs from alcohol abusers,normal donors, and alcohol treated cells. 2. the epigenetic mechanisms involved in alcohol-modulation of CB2 and GPR55 genes in normal MDDCs treated with alcohol. 3. the potential of HDACinhibitors and cannabinoid agonists to reduce inflammation and restore oxidative stress damage inMDDCs from alcohol users and normal MDDCs treated with alcohol.Thus, an understanding of thealcohol-associated epigenetic changes and its implications in immune modulation will have translationalsignificance for therapeutic targeting and control of AUDs.

date/time interval

  • February 1, 2015 - January 31, 2019

sponsor award ID

  • 4R00AA021264-03

local award ID

  • AWD000000005060

contributor

keywords

  • Acute
  • Agonist
  • Alcohol abuse
  • Alcohol dependence
  • Alcohol-Related Disorders
  • Alcohols
  • Alzheimer's Disease
  • American
  • Animal Model
  • Anti-Inflammatory Agents
  • Anti-inflammatory
  • Antioxidants
  • Area
  • Award
  • CNR1 gene
  • Cannabinoids
  • Cell Line
  • Cells
  • Cessation of life
  • Chronic
  • Cocaine
  • Communicable Diseases
  • Complex
  • Data
  • Dendritic Cells
  • Development
  • Development Plans
  • Disease
  • Drug Addiction
  • Ensure
  • Epigenetic Process
  • Figs - dietary
  • Generations
  • Genes
  • Genetic study
  • Goals
  • HDAC2 gene
  • Histone Acetylation
  • Histone Deacetylase Inhibitor
  • Histone Deacetylation
  • Histones
  • Human
  • Immune
  • Immune System Diseases
  • Immune system
  • Immunosuppression
  • Individual
  • Inflammation
  • Inflammatory
  • Investigation
  • Knowledge
  • Laboratory Research
  • Learning
  • Leukocytes
  • Mediating
  • Medical
  • Mentors
  • Mentorship
  • Mission
  • Molecular
  • National Institute on Alcohol Abuse and Alcoholism
  • Nerve Degeneration
  • Neurodegenerative Disorders
  • Neurons
  • Opioid Receptor
  • Oxidative Stress
  • Oxidative Stress Induction
  • Pharmaceutical Preparations
  • Phase
  • Physiological
  • Play
  • Prevention
  • Process
  • Production
  • Receptor Gene
  • Reporting
  • Research
  • Research Personnel
  • Research Proposals
  • Role
  • Self Administration
  • Solid
  • System
  • Testing
  • Therapeutic
  • Trichostatin A
  • Tumor Necrosis Factor-alpha
  • United States
  • Up-Regulation
  • Work
  • addiction
  • alcohol abuse therapy
  • alcohol abuser
  • alcohol effect
  • alcohol exposure
  • alcohol use disorder
  • base
  • career development
  • chromatin remodeling
  • effective therapy
  • experience
  • high risk
  • human CCR10 protein
  • human GPRC5C protein
  • immunoregulation
  • improved
  • in vivo
  • inhibitor/antagonist
  • innovation
  • interest
  • interleukin-12 subunit p40
  • macrophage
  • medical complication
  • meetings
  • monocyte
  • neuroinflammation
  • novel
  • novel therapeutics
  • prevent
  • receptor
  • skills
  • therapeutic target