The broad objective of this project is to elucidate key mechanistic and regulatory features of human pre-mRNA splicing, and its functional links to nonsense-mediated mRNA decay. Some of these mechanistic insights will be leveraged to develop targeted antisense oligonucleotide therapeutics, which can be used in the long term for clinical applications in precision medicine. The proposed experiments involve a broad range of experimental and computational approaches, including cell-free and cell-based assays, high-throughput RNA-sequencing and quantitative proteomics, bioinformatics, transgenic mouse models, and antisense pharmacology. The anticipated findings will facilitate therapeutic antisense oligonucleotide design for various diseases, besides expanding our fundamental knowledge of basic post-transcriptional mechanisms and regulation.

Public Health Relevance

These studies will substantially advance our current understanding of fundamental steps in the post-transcriptional control of gene expression, as well as influence the understanding, diagnosis, and treatment of various genetic diseases associated with defective splicing or nonsense mutations.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37GM042699-27
Application #
9177882
Study Section
Special Emphasis Panel (NSS)
Program Officer
Bender, Michael T
Project Start
1989-07-01
Project End
2022-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
27
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
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Paz, Sean; Krainer, Adrian R; Caputi, Massimo (2014) HIV-1 transcription is regulated by splicing factor SRSF1. Nucleic Acids Res 42:13812-23

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