Thursday, November 21, 2024
11/21/2024
ABSTRACT Retrotransposable elements (RTEs) are genomic elements that have the ability to “copy-and-paste” themselves into new locations within the genome. RTE mobilization can cause mutations and genomic instability. Many cellular mechanisms exist to repress RTE activity. Interestingly, it has been observed that neural stem and progenitor cells (NSPCs) show high levels of RTE activity. However, it is currently unknown whether this RTE activity is essential for normal development of the brain. Further, abnormally high RTE activity has been associated with a number of neurodevelopmental disorders. Causative roles for RTE expression and mobilization in neurodevelopmental disorders have not been identified. The long term objectives of this proposal are to understand whether RTE activation is necessary for normal development and whether RTE inhibition is a viable treatment for neurodevelopmental disorders. In my first specific aim, I will test the impact RTE expression and mobilization has on Drosophila brain development and on cerebral organoid development. Drosophila and cerebral organoids will be treated with Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to prevent RTE activity. Single-cell RNA sequencing will reveal the cell-type specific differences between control models and models treated with NRTIs. In my second aim, I will investigate the mechanism by which unrestricted RTE activity can cause microcephaly. Preliminary data shows increased NSPC death in a Drosophila model of microcephaly. I will determine whether this is true in multiple other microcephaly models and determine if DNA damage caused by RTE activation in Drosophila microcephaly models leads to the NSPC death observed. The proposed research will illuminate the role of RTE activity during neurodevelopment. Importantly, it will also provide crucial information to inform whether inhibition of RTEs during development is a viable therapeutic for microcephaly and other neurodevelopmental diseases that are caused by RTEs, thus prompting future pre-clinical studies.
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