Projects
Projects
One microRNA can control hundreds of mRNAs, making them powerful regulators of neuronal function and entire biological pathways and attractive targets in complex brain network disorders such as autism and epilepsy. In candidate-based approaches, we identified microRNAs that alter neuronal function and seizure susceptibility in mouse models. However, incomplete knowledge of microRNA function and regulation currently limits their use as therapeutic tools and targets in brain disorders. A major goal of the lab is to close these gaps in knowledge by revealing how microRNAs, that are often ubiquitously expressed and target hundreds of mRNAs, can confer specificity in the brain and are regulated by genetic, hormonal and environmental factors. We are using viral and transgenic mouse tools to identify cell type-specific mRNA targets of microRNAs and to study their cell type-specific functions in neuronal morphology, learning and memory, behavior and seizure susceptibility. Together, these studies will advance basic understanding of microRNA function, which is essential for the development of microRNA-based therapies for brain disorders with minimized side effects and maximized efficacy.
MicroRNAs are key regulators of neuronal function and cellular signaling networks and are frequently disrupted in neurological disease. To better understand their role in neurological diseases, we investigate microRNA-induced silencing in diverse forms of epilepsy and neurodevelopmental disorders, including catamenial epilepsy, a female-specific form of epilepsy, in which seizure frequency changes with the menstrual cycle, as well as neurodevelopmental disorders caused by single gene mutations and environmental factors. Building on this work we are developing microRNA-based strategies to correct pathological mechanisms underlying these disorders, harnessing both the power of endogenous microRNAs and the potential of highly specific artificial microRNAs.
The PI3K/mTOR pathway is often dysregulated in brain disorders. Our research focuses on the role of this signaling pathway in idiopathic and monogenic brain disorders, including Fragile X syndrome (FXS), one of the most common monogenic forms of intellectual disability and autism spectrum disorder, and tuberous sclerosis complex (TSC), a genetic syndrome associated with intractable epilepsy among other symptoms. In collaborations with basic and physician scientists at CCHMC, we use mouse models and human-derived cell lines and neurons to assess pharmacologic and genetic rescue strategies as well as the genetic underpinnings of phenotypic diversity in these disorders.
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