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We use in vivo and in vitro models of cerebrovascular injury and a range of techniques such as  in situ hybridization, immunoprecipitation, immunochemistry, high-throughput sequencing, microarrays, reporter assays, gain- or loss-of-function strategies, imaging, and bioinformatics to study RNA biology and function in brain damage.

LncRNAs and Regulation of Transcription

LncRNAs directly interact with regulatory proteins such as chromatin modifiers and transcription factors at genomic sites to alter the local transcriptional landscape. This influences gene expression and phenotypic outcomes. The key lncRNA-protein complexes that are differentially active in the normal versus injured brain are not yet fully known. What are their genomic targets and what specific actions do they perform at these sites? How do these activities influence the pathophysiology? Our lab is currently addressing these questions. Our long-term goal is to map the transcriptomic networks that are modulated by specific lncRNA-protein modules in response to cerebrovascular diseases such as stroke and vascular dementia.


Regulation of gene expression by enhancer RNAs in cerebrovascular injury

Enhancers undergo activity-dependent transcription to produce noncoding enhancer RNAs (eRNAs). Some of these eRNAs have been shown to play central roles in organizing functional interactions between the enhancers and their downstream gene targets and influence cellular outcomes. We recently identified several novel stroke-responsive eRNAs in the post-stroke cerebral cortex. Loss-of-function experiments resulted in pronounced molecular and phenotypic outcomes, which suggest important roles for the eRNAs in the post-stroke brain. Our work in this area is focused on identifying the molecular targets of these eRNAs, the cellular and physiological processes that they influence, and their sex-based expression and functional characteristics using in vitro and in vivo models of stroke. We are further extending this work to mouse models of vascular dementia to understand the roles of eRNAs in modulating gene expression networks in the subcortical regions of the brain during chronic cerebral hypoperfusion.

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Novel mRNA splice variants and protein isoforms in the post-stroke brain

One of the most important processes during transcription is the alternative splicing of the pre-RNA to produce multiple, distinct mRNAs. Alternative splicing enables the cell to generate a diverse complement of mRNAs from a limited number of genes to facilitate diversification of function, and such molecular and functional diversity has implications for development and disease. Recently, we identified several novel alternatively spliced mRNA isoforms whose expression was significantly altered in the cerebral cortex during stroke. Sequence analysis suggested that they have the potential to be translated into novel proteins. Altered spatiotemporal expression of such novel proteins may have important implications for the pathophysiological outcomes in stroke. Our current work is focused on investigating the putative translational products of the novel mRNAs, evaluating their cellular and subcellular distribution in the brain, identifying their functions and functional partners, and determining their expression patterns as a function of age and sex. Our overarching goal is to obtain a clearer understanding of the transcriptomic changes occuring in the post-stroke cortex and their significance to the post-stroke pathophysiology.

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