Browsing by Author "Miranda, Rajesh"

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    Research Project
    From FASD to AUDs: Strategies for Preventing Alcohol Addictions
    Neuroscience And Experimental Therapeuti; TAMHSC; https://hdl.handle.net/20.500.14641/511; DHHS-NIH-National Institute of Neurological Disorders and Stroke
    Project Summary/Abstract: 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.
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    Research Project
    Maternal Circulating miRNA Function In Fetal Alcohol Spectrum Disorders
    Neuroscience And Experimental Therapeuti; TAMHSC; https://hdl.handle.net/20.500.14641/511; DHHS-NIH-National Institute on Alcohol Abuse and Alcoholism (NIAAA)
    Project Summary Prenatal alcohol exposure (PAE) is the leading non-genetic cause of intellectual and other brain disabilities. However, fetal alcohol spectrum disorders (FASD), estimated to affect ~2-5% of school-aged children in the US, remain difficult to diagnose and to prevent. Our recent work (PMCID 5102408) identified several circulating microRNAs (miRNAs) in heavy alcohol-consuming pregnant women whose expression levels in the 2nd and 3rd trimester predicted adverse infant outcomes including craniofacial anomalies and neurobehavioral and growth deficits1. Specifically, Analysis of Variance (ANOVA) models identified 11 elevated plasma miRNAs in mothers whose infants were severely affected by alcohol consumption. Using Random Forest Analysis (RFA), we were further able to use a distinct group of miRNAs to classify infants apparently unaffected by ethanol exposure with affected infants as opposed to alcohol unexposed infants. Aside from their diagnostic value, it is unknown if these Maternal circulating miRNAs associated with Adverse Infant Outcomes (M-circmiRNA-aAIO) contribute to the developmental pathologies of FASD. Bioinformatic analysis suggests these circulating miRNAs potentially regulate important hub genes for STAT3 and ephrin signaling pathways, which are in turn known to control cycles of epithelial mesenchymal transition (EMT) crucial for normal embryogenesis and placental and fetal development. Therefore, my overarching hypothesis is that PAE impairs early development by interfering with the endocrine action of circulating maternal miRNAs on both the placenta and fetus. In my research proposal, using both human cell lines and in vivo mouse models, I will test the hypothesis that pathogenic levels of circulating miRNAs mediate effects of ethanol on placenta and fetus and that they control embryo growth and survival by regulating EMT-like behaviors of key placental and fetal cells. The long-term goals of this project will be to develop interventional strategies that exploit the biology of endocrine circulating miRNAs in mitigating negative outcomes due to PAE and other teratogens. My immediate goals will be to define the role of maternal miRNAs, which predict FASD outcomes, on placental and embryo growth and development. Aim 1: Determine the impact of M-circmiRNA-aAIOs on trophoblast growth, survival, migration and invasion under basal and ethanol exposed conditions. Aim 2: Determine the impact of M-circmiRNA-aAIOs on embryonic growth, death, and cellular maturation/differentiation under basal and ethanol exposed conditions. Aim 3: Determine the impact of M-circmiRNA-aAIOs on in vivo fetal development and neonatal outcomes. My studies are expected to uncover novel endocrine and pregnancy related functions of FASD-associated maternal systemic miRNAs and may provide novel therapeutic targets and non-invasive modalities to mitigate effects of PAE. Given its translational potential, this project will further my training as a physician-scientist interested in pursuing both clinical duties and research on early developmental disorders.