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Development of Next-Generation Mass Spectrometry-based de novo RNA Sequencing for all Modifications

Award Number: R01HG012853
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Development of Next-Generation Mass Spectrometry-based de novo RNA Sequencing for all Modifications - PROJECT SUMMARY An RNA sequence with all its diverse modifications constitutes ‘true’ information content of the RNA. Defects in RNA modifications account for >100 human diseases, such as breast cancer, type-2 diabetes and obesity, affecting millions of Americans. Despite its significance, the true sequence of a RNA, i.e., identity and location of each and every nucleotide building block (modified or not) within a full-length RNA, remains a mystery, mainly because of the lack of a general method to directly sequence any nucleotide, especially modified nucleotides (including unknown ones) at single-nucleotide resolution. No existing technology can sequence all modifications simultaneously to unfold the true RNA sequences at a large scale or the transcriptomic level. What complicates RNA modification studies is that >170 modification types have been discovered, and not all of nucleotide modifications are modified completely to 100% at their RNA sites. They are even undetectable by NGS-based technologies, which require the conversion of RNA to cDNAs that do not have any modification information. Tools to map RNA modifications are limited only to a few popular modifications, and can usually analyze only one modification type at a time. Mass spectrometry (MS) is currently the only technique that can characterize all RNA modifications; however, conventional MS methods lose information regarding the location and co-occurrence of modified nucleotides. To resolve these outstanding issues, we have recently developed a series of novel next generation mass spectrometry-based sequencing (NextGen MassSpec-Seq) approaches that can de novo directly sequence tRNAs without a cDNA and can sequence and quantify all nucleotide modifications simultaneously. For the duration of this proposal, we will further develop NextGen MassSpec-Seq to sequence tRNAs efficiently in different cellular and even disease conditions, make it scalable toward high throughput, and expand its application to simultaneously sequence and map all modifications quantitatively on any RNA type and at the transcriptomic level. Specifically, we propose to develop MS for large-scale de novo sequencing of full-length tRNAs, together with all diverse nucleotide modifications (Aim 1), empower MS to simultaneously sequence and quantify multiple RNA modifications, allowing quantitative mapping at single nucleotide and stoichiometric precision (Aim 2), scale up NextGen MassSpec-Seq and combine it with high-throughput NGS sequencing for direct sequencing of diverse RNA modifications at the transcriptomic level (Aim 3). Our tool will address a long- standing issue of how to reveal the ‘true” RNA sequences and provide a transformative tool for studying RNA modifications, which will promote better understanding of functions of post-transcriptional modifications and their correlations to RNA-related diseases and pandemics.


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: 2026 ( Subtotal = $617,230 )
2026	2026	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Human Genome Research	000	5	4/8/2026	NON-COMPETING CONTINUATION	$617,230
														Subtotal = $617,230

Issue Date FY: 2025 ( Subtotal = $676,673 )
2025	2025	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Human Genome Research	003	4	3/14/2025	NON-COMPETING CONTINUATION	$594,340
2025	2025	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Human Genome Research	004	4	4/28/2025	NON-COMPETING CONTINUATION	$66,038
2025	2024	NEW YORK INSTITUTE OF TECHNOLOGY	1855 BROADWAY	NEW YORK	NY	10023	NEW YORK	USA	Human Genome Research	000	2	12/20/2024	NON-COMPETING CONTINUATION	-$338,000
2025	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Human Genome Research	001	3	12/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$354,295
2025	2024	NEW YORK INSTITUTE OF TECHNOLOGY	1855 BROADWAY	NEW YORK	NY	10023	NEW YORK	USA	Human Genome Research	002	2	3/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $676,673

Issue Date FY: 2024 ( Subtotal = $637,486 )
2024	2024	NEW YORK INSTITUTE OF TECHNOLOGY	1855 BROADWAY	NEW YORK	NY	10023	NEW YORK	USA	Human Genome Research	001	2	2/5/2024	NON-COMPETING CONTINUATION	$0
2024	2024	NEW YORK INSTITUTE OF TECHNOLOGY	1855 BROADWAY	NEW YORK	NY	10023	NEW YORK	USA	Human Genome Research	000	2	1/18/2024	NON-COMPETING CONTINUATION	$585,448
2024	2024	NEW YORK INSTITUTE OF TECHNOLOGY	1855 BROADWAY	NEW YORK	NY	10023	NEW YORK	USA	Human Genome Research	002	2	8/22/2024	NON-COMPETING CONTINUATION	$52,038
														Subtotal = $637,486

Issue Date FY: 2023 ( Subtotal = $676,946 )
2023	2023	NEW YORK INSTITUTE OF TECHNOLOGY	NORTHERN BLVD	OLD WESTBURY	NY	11568	NASSAU	USA	Human Genome Research	001	1	3/16/2023	NEW	$0
2023	2023	NEW YORK INSTITUTE OF TECHNOLOGY	NORTHERN BLVD	OLD WESTBURY	NY	11568	NASSAU	USA	Human Genome Research	000	1	2/23/2023	NEW	$676,946
														Subtotal = $676,946

Grand Total All Awards = $2,608,335

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Development of Next-Generation Mass Spectrometry-based de novo RNA Sequencing for all Modifications

Award Number: R01HG012853

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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