Eleonora Gatta - US grants

PROJECT SUMMARY. Alcohol use disorder (AUD) is a complex brain disorder characterized by an array of persistent behavioral and neurochemical manifestations often comorbid with cognitive impairments. Several lines of evidence indicate that chronic alcohol exposure has a deleterious effect on the development and progression of cognitive decline and dementia, including Alzheimer?s disease (AD). Alcohol-induced epigenetic alterations (e.g., DNA hyper/hypo- methylation) exert long-lasting effects on gene expression. Yet, the epigenetic basis for transcriptomic changes resulting from AUD, their impact on cognitive impairments, and the development of AD neuropathology remains unclear. Alcohol stimulates the release of glucocorticoids, which in excessive amounts, disrupt neuronal function and contribute to age-related cognitive decline. Thus, alcohol augments the cognitive burden by contributing to key molecular mechanisms underlying neuropathology via glucocorticoid-mediated processes. Here, we propose to examine the glucocorticoid receptor (GR)-mediated molecular mechanisms through which chronic alcohol produces transcriptomic changes, including gene networks involved in the development of AD, in an animal model of alcohol dependence. We will use high-throughput sequencing techniques (CUT&RUN and ATAC-seq) and epigenetic expression manipulation via epigenetic editing (CRISPR/dCas9) to assess alcohol- induced changes in GR binding and consequent transcriptomic and behavioral changes (K99 phase) to further delve into the biological processes underlying the development of cognitive decline and neuronal pathology during aging (R00 phase). The innovative nature of this project combined with the outstanding research environment will help the applicant gain training in cutting-edge molecular and bioinformatic approaches and additional career development opportunities necessary for success as an independent alcohol researcher. Dr. Eleonora Gatta will receive training from a team of senior alcohol researchers and neuroscientists at UIC. The mentorship team, composed of Drs. S.C. Pandey (primary mentor), A. Guidotti, E.J. Glover, A. Lasek and M. Maienschein-Cline, will offer insights on experiment design, animal model of alcohol dependence, completion and analyses of big data sets as well as on professional and career development in alcohol research. In addition, the training plan contains considerable training on grant writing, oral presentations, ethics, as well as construction of bioinformatic pipelines that will be crucial to Dr. Gatta?s success as an independent researcher during the R00 phase. In addition to training provided by the mentoring team, Dr. Gatta will have access to resources in the Department of Psychiatry at UIC and in the Center for Alcohol Research on Epigenetics (CARE). Collectively, this K99/R00 application will identify novel brain mechanisms in the co-morbidity of AUD and AD by uncovering epigenetic mechanisms underlying increased susceptibility for cognitive decline and risk to develop AD neuropathology in individuals with AUD.