Alcohol use disorders are third leading cause of preventable death, accounting for approximately 90,000 preventable deaths each year (Danaei et al 2009). Nearly 50% deaths are secondary to diseases that are associated with inflammation and aberrant immune activation such as sepsis and alcoholic liver disease (Mokdad et al 2000). Recent discoveries find that alcohol activates the innate immune system in both the CNS and periphery. Thus, understanding the effects of alcohol on the immune system is critical to form a foundation of discovery leading to the understanding of both the pathology of alcoholism and numerous alcohol-associated diseases. We have found recently that alcohol activates the innate immune system through the ?master regulator? of innate immunity, HMGB1. In this proposal we aim to investigate the effects of alcohol on central and peripheral immune activation through HMGB1 and its companion cytokine IL-?. Using in vitro cell culture systems (Aim 1), in vivo experiments (Aim 2-3) and assessments in human alcoholics, burn patients and alcoholic hepatitis patients (Aim 4), we hope to gain an understanding of the immune effects of alcohol throughout the body. I will gain new laboratory experience with real time-PCR, enzyme-linked immunosorbant assays, co-immunoprecipitation, western blotting, intracerebral AAV5 viral injections, mass spectrometry, immunocytochemistry, and live fluorescent imaging. We also investigate a novel mechanism of cell-cell communication in this pathology, alcohol-induced release of pro-inflammatory microparticles. Further, we investigate the role of the PTEN/PI3K/Akt/mTOR pathway in the immune effects of alcohol, and study inhibitors of this pathway which may be novel therapeutic options. Our preliminary data strongly suggest that alcohol causes central and peripheral HMGB1 and IL-1? release in microparticles through a PTEN/PI3K/Akt/mTOR linked mechanism. This project also incorporates substantial career development with career and research mentoring from top tier researchers and clinicians, the learning of new experimental techniques, and course work to enhance clinical/translational expertise. Co-mentors Fulton T. Crews, PhD and Bruce Cairns MD provide a depth of basic science, clinical research, and career development mentorship that will help ensure the successful transition of the candidate to being a top independent translational researcher.
Alcohol abuse causes inflammation in the brain and throughout the body. The goal of this project is to better understand the way that alcohol affects the immune system, leading to alcoholism and alcohol related diseases. This project also tests potential drug treatments that will hopefully reduce the negative effects of alcohol of the immune system.
|Coleman Jr, Leon G; Zou, Jian; Qin, Liya et al. (2018) HMGB1/IL-1? complexes regulate neuroimmune responses in alcoholism. Brain Behav Immun 72:61-77|
|Coleman Jr, Leon G; Crews, Fulton T (2018) Innate Immune Signaling and Alcohol Use Disorders. Handb Exp Pharmacol 248:369-396|
|Crews, Fulton T; Lawrimore, Colleen J; Walter, T Jordan et al. (2017) The role of neuroimmune signaling in alcoholism. Neuropharmacology 122:56-73|
|Crews, Fulton T; Walter, T Jordan; Coleman Jr, Leon G et al. (2017) Toll-like receptor signaling and stages of addiction. Psychopharmacology (Berl) 234:1483-1498|
|Coleman Jr, Leon G; Zou, Jian; Crews, Fulton T (2017) Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7. J Neuroinflammation 14:22|