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Bridging Disparate Structural/Functional Scales: Multiscale Modeling of Genome Organization and of Viral RNA Frameshifting

Award Number: R35GM122562
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: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Bridging Disparate Structural/Functional Scales: Multiscale Modeling of Genome Organization and of Viral RNA Frameshifting - Abstract As advances in both experimental and computational biology lead to exciting discoveries in many ﬁelds of biology and biomedicine today, new avenues to diagnose and treat human disease are becoming a reality. Molecular dynamics and other simulation approaches play a key role in these connections by helping deﬁne the underlying biophysical mechanisms, at unprecedented resolution. The PI's computational biophysics lab focuses on solving fundamental structural and functional challenges concerning nucleic acids and their complexes (notably chromatin and RNA), in collaboration with experimentalists, by innovative molecular models and simulation methods using ideas from mathematics, computer science, engineering, biology, and chemistry. This MIRA project would continue to advance our fundamental understanding of genome organization and RNA motifs using multiscale models that bridge disparate spatial and temporal scales to generate biophysical insights into genome folding and cancer genomics, and RNA conformational landscapes/ viral mechanisms. For chromatin and chromosomes, modeled nucleosomes and their protein complexes at atomic resolution, and chromatin ﬁbers at the mesoscale, will be linked to data from genome-wide and cancer epigenomics studies to determine the modulation of chromatin higher-order structure in processes of aberrant gene expression. Speciﬁcally, we will focus on the structural role and mechanisms of proteins (like CTCF and H1) in gene looping and formation of topologically associated domains (TADs) and nuclear compartments in gene activation or repression in cancer cells. For RNA, our topological approach to modeling RNA secondary structure by coarse-grained graphs (RAG: RNA-As-Graphs), combined with atomic biophysical modeling, will delineate programmed ribosomal frameshifting mechanisms in RNA coronaviruses and other viruses, and advance the RNA motif atlas. Speciﬁcally, conformational dynamics associated with the RNA frameshifting element of SARS-CoV-2, along with evolutionary and biophysical analysis and chemical reactivity experiments, will describe frameshifting transitions and identify/test experimentally structure-altering mutations that may hamper frameshifting. RAG will also be applied to deﬁne a virus topology atlas and explore virus motifs from an RNA repertoire point of view, to help understand the RNA motif universe and advance novel RNA design. The unraveled biophysical mechanisms in genome organization and RNA frameshifting/conformational repertoire have translational ramiﬁcations for human cancers and viral infections by coronaviruses or HIV. For cancer therapy, a targeted re-expression of silenced genes may be possible by chromatin topological changes (e.g., loop dissolution) and RNA editing. For viral RNA infections, new strategies for gene and anti-viral therapy emerge from this research, feasible by modern RNA editing technologies. The resulting multidisciplinary computational paradigms are widely applicable to other biomolecular processes and will be shared with the community at large.


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 = $526,702 )
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	8	5/22/2025	NON-COMPETING CONTINUATION	$526,702
2025	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	7	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $526,702

Issue Date FY: 2024 ( Subtotal = $650,349 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	002	7	6/4/2024	NON-COMPETING CONTINUATION	$525,349
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	003	7	9/4/2024	SUPPLEMENT FOR EXPANSION	$125,000
2024	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	6	5/14/2024	COMPETING CONTINUATION	$33,833
2024	2021	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	5	5/14/2024	NON-COMPETING CONTINUATION	-$33,833
														Subtotal = $650,349

Issue Date FY: 2023 ( Subtotal = $570,308 )
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	6	5/15/2023	COMPETING CONTINUATION	$570,308
														Subtotal = $570,308

Issue Date FY: 2021 ( Subtotal = $469,500 )
2021	2021	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	5	6/14/2021	NON-COMPETING CONTINUATION	$469,500
														Subtotal = $469,500

Issue Date FY: 2020 ( Subtotal = $466,229 )
2020	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	4	7/20/2020	NON-COMPETING CONTINUATION	$466,229
														Subtotal = $466,229

Issue Date FY: 2019 ( Subtotal = $461,821 )
2019	2019	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	3	6/13/2019	NON-COMPETING CONTINUATION	$461,821
														Subtotal = $461,821

Issue Date FY: 2018 ( Subtotal = $457,642 )
2018	2018	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	2	6/26/2018	NON-COMPETING CONTINUATION	$457,642
														Subtotal = $457,642

Issue Date FY: 2017 ( Subtotal = $422,208 )
2017	2017	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	1	8/30/2017	NEW	$422,208
														Subtotal = $422,208

Grand Total All Awards = $4,024,759

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Bridging Disparate Structural/Functional Scales: Multiscale Modeling of Genome Organization and of Viral RNA Frameshifting

Award Number: R35GM122562

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: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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