The primary goal of this mentored career development K99 phase is to develop the knowledge, skills and experience required to progress to an independent investigator R00 phase. The proposed career development plan includes the participation in seminars and scientific meetings to gain knowledge on the current alcohol addiction research, improving laboratory research skills, and mentored learning to ensure a successful transition to independence. This will create a solid platform of knowledge and skills. The mentored proposal under the mentorship of Dr. Madhavan Nair will encourage hypothesis driven research and independent investigation. In the United States, 18 million Americans suffer from alcohol use disorders (AUD). Only 7.1% of these individuals received any treatment in the past year; and alcohol abuse (AA) contributes to 5% of death annually. AA can contribute to a higher risk of infectious diseases and other undesirable medical conditions involving complex interactions between the direct effects of alcohol and its toxic metabolites on various immune 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 is relevant to the mission and research interests of NIAAA since it will elucidate mechanisms underlying the biomedical effects of alcohol in human immune cells and also combines alcohol with innovative research areas including CBRs and epigenetics. The proposed research that leads to the independent R00 phase of the award is aimed to dissect the role of alcohol-associated epigenetic mechanisms in immune modulation of cannabinoid genes. In recent years, chromatin remodeling has emerged as an important regulatory mechanism for drug addiction and also in development of neurodegenerative disorders. Further, HDAC inhibitors (HDACi) have been known to modulate genes involved in drug addiction such as the ? opioid receptor gene (MOR), and decrease 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-derived dendritic cells (MDDCs), and the mechanisms may be mediated by HDACs and oxidative stress. The specific 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 HDAC inhibitors and cannabinoid agonists to reduce inflammation and restore oxidative stress damage in MDDCs from alcohol users and normal MDDCs treated with alcohol.Thus, an understanding of the alcohol-associated epigenetic changes and its implications in immune modulation will have translational significance for therapeutic targeting and control of AUDs.

Public Health Relevance

Approximately 18 million Americans suffer from alcohol use disorders (AUDs), and one of the least appreciated medical complications of alcohol abuse is its effect on the immune system. To date, there is a growing demand for more effective treatments for AUDs, and research to elucidate the molecular mechanisms of the effects of alcohol on immune modulation; therefore, this research proposal herein will study the effects of alcohol and the role of epigenetic mechanisms such as histone deacetylation on the modulation of cannabinoid genes (CBRs) in human immune cells. A long term benefit of elucidating the molecular mechanisms associated with the interaction of alcohol with HDACs and CBRs will be the application of what is learned in this study to aid in the development of novel therapeutics for the prevention of AUDs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Transition Award (R00)
Project #
5R00AA021264-05
Application #
9212071
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lin, Li
Project Start
2013-02-15
Project End
2018-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
5
Fiscal Year
2017
Total Cost
$216,974
Indirect Cost
$67,336
Name
Florida International University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
071298814
City
Miami
State
FL
Country
United States
Zip Code
33199
Parira, Tiyash; Laverde, Alejandra; Agudelo, Marisela (2017) Epigenetic Interactions between Alcohol and Cannabinergic Effects: Focus on Histone Modification and DNA Methylation. J Alcohol Drug Depend 5:
Parira, Tiyash; Figueroa, Gloria; Laverde, Alejandra et al. (2017) Novel detection of post-translational modifications in human monocyte-derived dendritic cells after chronic alcohol exposure: Role of inflammation regulator H4K12ac. Sci Rep 7:11236
Figueroa, Gloria; Parira, Tiyash; Laverde, Alejandra et al. (2016) Characterization of Human Monocyte-derived Dendritic Cells by Imaging Flow Cytometry: A Comparison between Two Monocyte Isolation Protocols. J Vis Exp :
Agudelo, Marisela; Figueroa, Gloria; Parira, Tiyash et al. (2016) Profile of Class I Histone Deacetylases (HDAC) by Human Dendritic Cells after Alcohol Consumption and In Vitro Alcohol Treatment and Their Implication in Oxidative Stress: Role of HDAC Inhibitors Trichostatin A and Mocetinostat. PLoS One 11:e0156421
Nair, Madhavan P; Figueroa, Gloria; Casteleiro, Gianna et al. (2015) Alcohol Versus Cannabinoids: A Review of Their Opposite Neuro-Immunomodulatory Effects and Future Therapeutic Potentials. J Alcohol Drug Depend 3:
Agudelo, Marisela; Figueroa, Gloria; Yndart, Adriana et al. (2015) Alcohol and Cannabinoids Differentially Affect HIV Infection and Function of Human Monocyte-Derived Dendritic Cells (MDDC). Front Microbiol 6:1452
Agudelo, Marisela; Khatavkar, Pradnya; Yndart, Adriana et al. (2014) Alcohol abuse and HIV infection: role of DRD2. Curr HIV Res 12:234-42