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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Bender, Michael T
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Cold Spring Harbor Laboratory
Cold Spring Harbor
United States
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Wong, Mandy S; Kinney, Justin B; Krainer, Adrian R (2018) Quantitative Activity Profile and Context Dependence of All Human 5' Splice Sites. Mol Cell 71:1012-1026.e3
Sinha, Rahul; Kim, Young Jin; Nomakuchi, Tomoki et al. (2018) Antisense oligonucleotides correct the familial dysautonomia splicing defect in IKBKAP transgenic mice. Nucleic Acids Res 46:4833-4844
Sheng, Lei; Wan, Bo; Feng, Pengchao et al. (2018) Downregulation of Survivin contributes to cell-cycle arrest during postnatal cardiac development in a severe spinal muscular atrophy mouse model. Hum Mol Genet 27:486-498
Aznarez, Isabel; Nomakuchi, Tomoki T; Tetenbaum-Novatt, Jaclyn et al. (2018) Mechanism of Nonsense-Mediated mRNA Decay Stimulation by Splicing Factor SRSF1. Cell Rep 23:2186-2198
Doktor, Thomas Koed; Hua, Yimin; Andersen, Henriette Skovgaard et al. (2017) RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns. Nucleic Acids Res 45:395-416
Wu, Xingxing; Wang, Shu-Huei; Sun, Junjie et al. (2017) A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy. Hum Mol Genet 26:2768-2780
Allemand, Eric; Myers, Michael P; Garcia-Bernardo, Jose et al. (2016) A Broad Set of Chromatin Factors Influences Splicing. PLoS Genet 12:e1006318
Nomakuchi, Tomoki T; Rigo, Frank; Aznarez, Isabel et al. (2016) Antisense oligonucleotide-directed inhibition of nonsense-mediated mRNA decay. Nat Biotechnol 34:164-6
Krainer, Adrian R (2015) Splicing: still so much to learn. RNA 21:500-1
Hua, Yimin; Liu, Ying Hsiu; Sahashi, Kentaro et al. (2015) Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models. Genes Dev 29:288-97

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