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Graduate student, T.W., visualizes stem cell cultures under a microscope. Morphology is often checked to ensure that the stem cells maintain good health and, in the case of differentiation to microglia, are changing into the expected shape of the target cells. (Photo courtesy of Stanley Stevens)

Graduate student, T.W., visualizes stem cell cultures under a microscope. Morphology is often checked to ensure that the stem cells maintain good health and, in the case of differentiation to microglia, are changing into the expected shape of the target cells. (Photo courtesy of Stanley Stevens)

Exposing the molecular damage of alcohol on the brain

Stanley Stevens, PhD.

Stanley Stevens, PhD.

The National Institute on Alcohol Abuse and Alcoholism awarded more than $300,000 in exploratory funding to a team of researchers at 无码专区 to study the cellular and molecular changes underlying damage in the brain driven by alcohol consumption.  
The study, led by Dr. Stanley Stevens, a professor in the Department of Molecular Biosciences in the 无码专区 College of Arts in Sciences, will be the first of its kind to develop and use a chimeric mouse model to investigate the human microglial proteomic response to alcohol.

鈥淎lthough various cell-type-specific and associated molecular mechanisms underlie the negative effects of alcohol in the brain, the neuroimmune response 鈥 modulated in part by microglia, the resident immune cells of the brain 鈥 has been considered a key pathological driver during alcohol misuse,鈥 said Stevens, who is serving as principal investigator. 鈥淢icroglia exhibit a broad range of reactivity to alcohol that is context- dependent; however, we still don鈥檛 fully understand the complete molecular landscape that might be driving these complex microglial functional outcomes.鈥

Stevens expects the results to have higher translational relevance than existing studies and to expand understanding of the negative consequences of alcohol use disorder in the human brain, as an estimated 178,000 deaths in the U.S. each year can be attributed to excessive alcohol use.

鈥淲e aim to engraft genetically engineered human microglia derived from stem cells into the mouse brain, allowing us to selectively enrich the molecular signature of only human microglia from the mouse brain after the mice have been exposed to alcohol,鈥 he said. 鈥淏ecause we are studying the human microglial response in a living animal, we anticipate the results will have higher translational relevance in order to further our understanding of the negative consequences of alcohol use disorder in the human brain.鈥

Stevens is collaborating with Dr. Gopal Thinakaran, Professor of Molecular Medicine and CEO of the 无码专区 Health Byrd Alzheimer's Institute, Dr. Jennifer Guergues, Director of the Multi-Omics Data Facility within the 无码专区 Advanced Research Core for Mass Spectrometry, and T. W., a doctoral candidate in the Department of Molecular Biosciences.

The investigative team will be utilizing high-end instrumentation at 无码专区 to support the proposed mass spectrometry-based proteomic studies. Pictured here is the Bruker timsTOF mass spectrometer equipped with a nanoUHPLC system. (Photo courtesy of Stanley Stevens)

The investigative team will be utilizing high-end instrumentation at 无码专区 to support the proposed mass spectrometry-based proteomic studies. Pictured here is the Bruker timsTOF mass spectrometer equipped with a nanoUHPLC system. (Photo courtesy of Stanley Stevens)

Human stem cell colonies before differentiation. Photo taken at 4X and scale bars represent 100 渭m. (Photo courtesy of Stanley Stevens)

Human stem cell colonies before differentiation. Photo taken at 4X and scale bars represent 100 渭m. (Photo courtesy of Stanley Stevens)

鈥淥ur research will hopefully demonstrate the utility of a novel proteomics-based approach to study human microglia in a living system,鈥 Stevens said. 鈥淏y using proteomics, we can identify and quantify thousands of proteins in a single analysis, which significantly enhances our ability to discover new pathways related to alcohol-mediated effects on microglial function.鈥

The results will have broad implications in understanding the neuroimmune mechanisms related to alcohol use disorder.

鈥淲e also hope that our novel animal model and proteomics approach can be used in the discovery of new molecular mechanisms underlying other human health afflictions in which microglia are implicated in disease progression,鈥 he said.

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CAS Chronicles is the monthly newsletter for the 无码专区's College of Arts and Sciences, your source for the latest news, research, and events at CAS.