Alcohol use disorder (AUD), characterized by uncontrollable alcohol consumption due to physical and psychological dependence, affects approximately 14.1 million people in the U.S. Despite the related public health issues and associated economic costs - an estimated $249 billion annually - pharmacological treatment options for AUD have advanced only minimally since 2004. This underscores the urgent need for novel therapeutic targets.
In an effort to uncover some of these potential targets, the National Institute on Alcohol Abuse and Alcoholism at the National Institutes of Health awarded a two-year, $407,468 grant to Dawei Li, Ph.D., from the Texas Tech University Health Sciences Center (TTUHSC) School of Medicine and Graduate School of Biomedical Sciences. In this pilot study, Li's laboratory will seek to identify new neurobiological (nervous system) factors for potential intervention, including a possible link between endogenous retroviruses (ERVs) and neuroinflammation.
Increased interferon (proteins released in cells due to a virus) signaling and activation of inflammatory pathways have been established in both individuals with AUD and alcohol-preferring animals. However, the mechanisms to reverse or modify these neuroimmune abnormalities are not well understood, creating a critical need to identify new neurobiological factors for potential intervention.
Neuroinflammation has been observed in the brains of individuals with AUD. In this pilot study, we will explore a new idea: whether there is a connection between ERVs and the neuroinflammation seen in AUD in a pilot sample."
Dawei Li, Ph.D., Texas Tech University Health Sciences Center (TTUHSC) School of Medicine and Graduate School of Biomedical Sciences
Although ERVs are silenced in most cases, certain environmental triggers can reactivate some of them. Once reactivated, host cells may recognize some ERVs as foreign due to their viral nature, which triggers inflammatory immune responses. Li said ERVs represent a promising area of investigation due to their roles in modulating immune responses and their contributions to inflammation.
ERVs make up eight percent of the human genome and consist of more than 400,000 distinct elements derived from ancient retroviral infections that have integrated into human genomes. These sequences can disrupt host cell functions and may reactivate in response to various environmental triggers.
"Our proposed model suggests that, although typically silenced, specific ERVs can be transcriptionally activated by chronic and excessive alcohol exposure, leading to inflammatory immune dysregulation in AUD," Li explained. "We aim to investigate the role of ERV expression and ERV genotypes in the AUD pathophysiology through our innovative bioinformatics platform, a process which enables precise genotyping and expression quantification of individual ERVs."
Utilizing pilot RNA and genome sequencing datasets from AUD patients, Li said he will pursue two goals: identifying distinct ERVs whose expression correlates with AUD, and identifying ERV variants whose genotypes are associated with AUD.
By leveraging existing datasets, innovative analytic tools and computing resources, Li said his lab's analyses seek to assess the ERV landscape at a genome-wide level. The outcomes he anticipates finding include identifying transcriptionally activated ERV transcripts and associated ERV variants that could help refine a new computer platform for future studies.
Li believes further research building on this pilot study will help in the development of therapeutic strategies by revealing ERV-related inflammatory pathways for targeted treatments, including repurposing FDA-approved anti-retroviral or anti-inflammatory drugs, or developing new agents aimed at mitigating ERV-driven inflammation. He said establishing the connection between ERVs and AUD will provide focus and supportive data for subsequent in-depth studies.
"If a link is identified, it could lead to an avenue for treatments that re-silence ERVs and for the development of molecular diagnosis of AUD," Li said. "However, any findings from this pilot study will need to be replicated in larger samples and carefully studied to understand their underlying biology."
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