Paula Grabowski

My laboratory has had a longstanding interest in the regulation of alternative pre-mRNA splicing in mammalian cells. As a graduate student with Thomas Cech at the University of Colorado, I characterized the splicing and autocyclization reactions of the Group I intron of the pre-ribosomal RNA of Tetrahymena, which was the first example of a self-splicing ribozyme. As a postdoctoral fellow working with Phillip Sharp at MIT, I developed an affinity selection approach to purify the constituents of the human spliceosome, which provided insights into its dynamic assembly pathway and chemical reaction mechanism. At Brown University, my laboratory provided novel support for the exon definition hypothesis by demonstrating the proportionality of the strength of base pairing of U1 small nuclear ribonucleoprotein complex at the 5´splice site on the rate of branch point formation at the upstream intron. At the University of Pittsburgh, my group has focused on the tissue specific regulation of alternative splicing. We have studied the mechanisms of several splicing factors in depth, including Polypyrimidine Tract Binding protein (PTB), hnRNP A1 and CUGBP2. To gain insights into the underlying splicing codes for each of these factors, we have used bioinformatics to expand the identification and testing of additional candidate target RNAs in the genome. Our current work aims to understand the plasticity of alternative splicing as this relates to the observed changes in splicing patterns that occur when cells are exposed to conditions of stress or stimulation. Current model systems involve neuronal cells subject to stimulation and cells undergoing viral infection. We are interested in understanding the mechanisms by which the plasticity of splicing can be modulated by cellular events, and how imbalances in its fine-tuned regulation can lead to neurodegenerative disease, aging, cancer and viral pathogenesis.

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Latest work with IntechOpen by Paula Grabowski

RNA functions broadly as informational molecule, genome, enzyme and machinery for RNA processing. While these functions reflect ancient activities, they also remain vital components of contemporary biochemical pathways. In eukaryotic cells RNA processing impacts the biogenesis of RNA molecules of essentially every shape and function. The collection of articles in this volume describes the current state of understanding of the broad array of RNA processing events in animal and plant cells, key unanswered questions, and cutting edge approaches available to address these questions. Some questions discussed in this volume include, how viruses subvert the RNA processing machinery of the host cell, how the coordination of co-transcriptional RNA processing is regulated at the level of chromatin, the status of RNA processing in plant organelles, and how micro RNA machinery is biosynthesized and regulated.

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