Prenatal alcohol exposure (PAE) is a leading cause of intellectual and other brain disabilities, contributing to an estimated prevalence of Fetal Alcohol Spectrum Disorder (FASD) at between 1 and 5% of school-aged children in the US. Despite prevention guidelines, alcohol use during pregnancy continues to be a problem, and consequently, FASD is difficult to prevent. Behind every child with an FASD is an adult with unmet mental health needs that result in risky patterns of alcohol consumption or an Alcohol Use Disorder (AUDs). Therefore, preventing FASD requires preventing risky alcohol consumption in adults. Preventing AUDs is challenging due to the paucity of effective medications. In this application, I propose a transitioning plan in which I complement my passion for the study of FASD (the F99 phase) with the study of AUDs (the K00 phase), with the expectation that the route to preventing FASD lies through preventing AUDs. However, in both phases, I plan to pursue my interests in the mediating biology of non-protein-coding RNAs. In the first phase of my predoctoral studies, I focused on Oct4/Pouf51, a transcription factor that is a key determinant of stem cell identity, and target of ethanol. I also identified a novel pseudo- gene duplication of the Oct4/Pou5f1 locus, encoding a long non-coding RNA that I termed, Oc4pg9 lncRNA. Oct4pg9 lncRNA is upregulated in neural stem cells (NSCs), following ethanol exposure. I found that Oct4pg9 lncRNA mediates many maturational effects of ethanol on NSCs. In the F99 phase, I plan to assess, using single-cell RNA sequencing, whether the expression of Oct4pg9 lncRNA and Oct4/Pou5f1 marks unique non-overlapping NSC subpopulations. Using an in vivo murine model for PAE, I plan to determine the extent to which ethanol exposure disrupts, at the cellular level, the association between Oct4Pou5f1 and Oct4pg9, leading to the emergence of new NSC subpopulations with aberrant maturation signatures. In the K00 phase, I will transition to the field of adult alcoholism and continue studying the regulation and function of lncRNAs in the context of AUDs. This research direction will focus on developing and behaviorally phenotyping mouse models of AUD-sensitive lncRNAs. Additionally, I will utilize transcriptomic signatures and high-throughput behavioral screening to identify and test candidate compounds that show promise in decreasing excessive alcohol consumption. This proposal provides a research and training plan for a transition from predoctoral FASD training to post-doctoral training in the biology of adult alcoholism, with the aim of developing an independent research program in the field of adult alcoholism.
Prenatal Alcohol Exposure (PAE), the leading cause of developmental disabilities, is difficult to prevent because adults, including pregnant women, with unmet mental health needs engage in risky patterns of alcohol consumption or have Alcohol Use Disorders (AUDs). The proposal seeks to understand the role of long non-coding RNAs in mediating alcohol effects on the developing brain (F99 phase) and in regulating alcohol-seeking behavior in adults (K00 phase), and will provide the applicant with training in drug repurposing and medications development for AUDs. This proposal is consistent with the goals of RFA-NS-19-011 to ?support a defined pathway across career stages for outstanding graduate students from diverse backgrounds?, since it will facilitate my transition from studying FASD to studying AUDs, and with the NIAAA mission, as it will facilitate development of an independent academic career with a focus on AUDs.
