Circular RNAs (circRNAs) are an emerging class of RNA molecules with potential for prolonged expression due to their inaccessibility to exonucleases. Recent studies dissecting circRNA biogenesis have found inverted repeat sequences such as ALU repeats in humans, flanking a large number of exons that are subject to circularization and have shown these cis-elements are essential for their circularization. CircRNA formation also requires both components of the standard pre-mRNA splicing machinery and canonical splicing signals, such as the polypyrimidine tract, and branch point. Although they have been largely demonstrated to have regulatory potential, recent studies have demonstrated that they can be translated. In the mammalian brain, circRNAs appear to be highly abundant and dynamically regulated by development and plasticity. In particular, they appear to be enriched at the synapses and during neuronal differentiation and development. Despite these exciting advances, no systems for efficient biogenesis of synthetic circRNAs in animal models have been developed to date. Host factors involved in regulating the formation of circRNAs in a spatio-temporal manner are also not well understood.
Specific aims for the current proposal are focused on engineering circRNA expression systems, studying factors affecting circRNA biogenesis in the brain and the efficiency as well as potential toxicity of circRNA biogenesis in a mouse model of RNA-induced neurotoxicity. Overall, the current proposal will help develop new strategies for efficient biogenesis of circRNAs in animal models, which are likely to help understand factors affecting circRNA biogenesis in the mammalian brain as well as usher in a new class of nucleic acid therapeutics based on circular RNAs.

Public Health Relevance

Project Summary Circular RNAs (circRNAs) are an emerging class of RNA molecules with potential for prolonged expression. The current proposal will help develop new strategies for efficient production of circRNAs in animal models, which are likely to help understand factors affecting circRNA formation in the mammalian brain as well as usher in a new class of nucleic acid therapeutics based on circular RNAs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS099371-01
Application #
9218392
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Gubitz, Amelie
Project Start
2017-08-01
Project End
2022-04-30
Budget Start
2017-08-01
Budget End
2018-04-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Wilusz, Jeremy E (2018) A 360° view of circular RNAs: From biogenesis to functions. Wiley Interdiscip Rev RNA 9:e1478
Mestre, Humberto; Hablitz, Lauren M; Xavier, Anna Lr et al. (2018) Aquaporin-4-dependent glymphatic solute transport in the rodent brain. Elife 7:
Liang, Dongming; Tatomer, Deirdre C; Luo, Zheng et al. (2017) The Output of Protein-Coding Genes Shifts to Circular RNAs When the Pre-mRNA Processing Machinery Is Limiting. Mol Cell 68:940-954.e3