Grant: Project Grant

When mammalian genes are transcribed into precursor messenger (m)RNA, the process of splicing joins the exons (coding segments) and excises the introns (non-coding segments) to produce mature mRNAs that can be translated into proteins. We have shown that for more than 90% of human genes, exons are spliced in different combinations to generate different mRNA isoforms through a process known as alternative splicing. Alternative splicing is a key regulatory process that controls virtually every aspect of human physiology and underlies many human disease states. However, the full repertoire of factors underlying the control of alternative splicing is not known, and the functions of the vast majority of splice variants are also not understood. Hindering progress in addressing these challenges is the lack of effective tools enabling the targeted and controlled modulation of alternative splicing events associated with physiologically-normal and disease-associated biological pathways and processes. To address these goals, we will develop and apply a CRISPR-based RNA tethering approach to systematically screen for new splicing modulators, and harness the new modulators for the manipulation of target alternative splicing events in both functional genomic and ultimately therapeutic-based applications.