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Pre-mRNA intronic structures in trans factor binding and alternative splicing

Award Number: R35GM142851
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Pre-mRNA intronic structures in trans factor binding and alternative splicing - Project Summary Splicing is the process of removing intronic regions from a precursor messenger RNA (mRNA) and combining exons into a mature transcript. Alternative splicing results in differential intron removal, producing multiple alternatively spliced isoforms arising from a common precursor mRNA. The dysregulation of splicing is estimated to underlie at least 15% of human diseases, and is likely to contribute to many more. Splice reactions are performed by the spliceosome, an RNA protein complex that is assembled onto precursor mRNA in stages. The final activity of the spliceosome is influenced by a combination of trans-acting spliceosome factors and cis elements within the precursor mRNA. However, factors involved in cis element function, like sequence motifs and RNA structure folds, are not fully understood, and a majority of such elements remain unidentified. This is particularly true for branchpoint selection, an essential early stage of spliceosome assembly within the intron around the catalytic adenosine. Although the branchpoint is loosely recognized as a highly degenerate sequence motif, it influences downstream splice site selection. My first goal is to elucidate the impact of RNA structure on branchpoint selection by focusing on RNA structure-mediated binding by the spliceosome associated SF3B complex. To do so, I will develop RNA secondary structure models for SF3B-dependent precursor RNAs to identify enriched structural motifs. My work will entail the first large-scale derivation of intronic secondary structures, including branchpoint regions, which will aid in better understanding of how RNA structures around cis regulatory elements influence splicing. My second goal is to develop a system to identify cis splicing regulatory elements and rapidly test their functional significance. To identify regulatory elements, I will identify cis features on mRNAs, including protein binding sites, conservation and RNA secondary structure, and use machine learning to discover novel signatures of functionally relevant cis regulatory regions. The functional impact of such sites on alternative splicing will be experimentally tested through use of antisense oligonucleotide (ASO) that can block or inhibit the regulatory region. I will set up a positive feedback loop where I can predict cis splice regulatory elements and immediately test their impact on splicing with ASOs, incorporating the test results back into the model to improve predictions. This system will lead to accurate prediction of cis regulatory splicing elements within any gene of interest. Accurate identification of cis elements will improve our ability to understand co-regulation of alternative splicing. The long-term vision of my research is to demystify the splicing code by clarifying the role of RNA structure in splicing and developing a powerful system to identify functional cis regulatory splicing elements and test their activity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $368,463 )
2025	2025	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Biomedical Research and Research Training	000	5	5/7/2025	NON-COMPETING CONTINUATION	$368,463
														Subtotal = $368,463

Issue Date FY: 2024 ( Subtotal = $368,463 )
2024	2024	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Biomedical Research and Research Training	000	4	5/14/2024	NON-COMPETING CONTINUATION	$368,463
														Subtotal = $368,463

Issue Date FY: 2023 ( Subtotal = $365,570 )
2023	2023	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Biomedical Research and Research Training	000	3	5/15/2023	NON-COMPETING CONTINUATION	$365,570
														Subtotal = $365,570

Issue Date FY: 2022 ( Subtotal = $368,463 )
2022	2022	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Biomedical Research and Research Training	000	2	5/5/2022	NON-COMPETING CONTINUATION	$368,463
														Subtotal = $368,463

Issue Date FY: 2021 ( Subtotal = $366,211 )
2021	2021	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Biomedical Research and Research Training	000	1	7/19/2021	NEW	$366,211
														Subtotal = $366,211

Grand Total All Awards = $1,837,170

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Pre-mRNA intronic structures in trans factor binding and alternative splicing

Award Number: R35GM142851

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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