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Control of Translation in Herpesvirus Infected Cells - Resubmission - 1

Award Number: R01GM056927
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: 05/01/1999
PERIOD OF PERFORMANCE END DATE: 12/31/2026

Group Awards By:

View Award Description

Control of Translation in Herpesvirus Infected Cells - Resubmission - 1 - 7. PROJECT SUMMARY / ABSTRACT Regulation of gene expression at the level of translation allows cells and organisms to respond swiftly to physiological stress and changing environments. Indeed, differential translation of capped, polyadenylated mRNAs by eukaryotic ribosomes plays a critical role in biological processes vital for human health, including normal cell growth, differentiation, development, learning and memory, and responses to physiological stress including virus infection. Viral model systems have proven useful in elaborating cellular translational control strategies because their replication is absolutely reliant upon virus mRNA translation by host ribosomes. Here, we utilize a herpesvirus family member, human cytomegalovirus (HCMV), to probe the complex circuitry regulating mRNA translation. Although innocuous in healthy individuals, HCMV is a widespread, opportunistic pathogen responsible for severe disease among the immunocompromised, including organ transplant recipients and AIDS patients. In addition, congenital HCMV infection is the leading viral cause of birth defects in newborns. Our long-term overall objective is to understand the mechanism(s) through which HCMV manipulates the cellular translational machinery to control viral replication. A fundamental step regulating protein synthesis in HCMV-infected cells involves ribosome recruitment to the 5'-end of m7G-capped virus and host mRNAs. This typically involves 5'-cap-recognition by a translation initiation factor complex containing the cap-binding protein eIF4E followed by loading the eIF3-bound 40S ribosome. Unexpectedly, an alternative form of 40S ribosome loading relying upon cap-recognition by a specific eIF3 subunit, eIF3d, has been described that bypasses the need for eIF4E and is distinctly regulated. Preliminary results establish that targeting eIF3d selectively inhibited HCMV replication, reduced polyribosome abundance and interfered with expression of essential virus late genes and a host gene expression signature indicative of chronic ER stress that fosters HCMV reproduction. Based on our preliminary results, we hypothesize that eIF3d-dependent cap- recognition is hijacked to exploit virus-induced ER-stress and switching between eIF4E and eIF3d-responsive translation differentially tunes virus and host gene expression in infected cells. This hypothesis is tested in three specific aims designed to: i) determine how HCMV infection impacts eIF3d accumulation and sub-cellular distribution; ii) define the mechanism whereby eIF3d selectively shapes the gene expression landscape in HCMV-infected cells; and iii) decipher how eIF3d activity is regulated in HCMV-infected cells. The project is impactful because how non-canonical translation initiation mechanisms involving eIF3d regulate differential mRNA translation during stress responses like virus infection remains largely unknown and represents a significant knowledge gap poised to reveal new biology and therapeutic opportunities for interfering with virus replication or vaccine development. Furthermore, it will provide insight into fundamental translational control mechanisms important in human diseases, like cancer and diabetes, where protein production is dysregulated.


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 = $436,140 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	001	21	3/11/2026	NON-COMPETING CONTINUATION	$43,614
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	21	12/19/2025	NON-COMPETING CONTINUATION	$392,526
														Subtotal = $436,140

Issue Date FY: 2025 ( Subtotal = $436,140 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	001	20	8/14/2025	NON-COMPETING CONTINUATION	$43,614
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	20	12/13/2024	NON-COMPETING CONTINUATION	$392,526
														Subtotal = $436,140

Issue Date FY: 2024 ( Subtotal = $436,140 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	19	12/7/2023	NON-COMPETING CONTINUATION	$392,526
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	001	19	7/15/2024	NON-COMPETING CONTINUATION	$43,614
														Subtotal = $436,140

Issue Date FY: 2023 ( Subtotal = $436,140 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	18	12/28/2022	COMPETING CONTINUATION	$436,140
														Subtotal = $436,140

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2019	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	17	8/2/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	17	2/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $399,509 )
2019	2019	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	17	1/17/2019	NON-COMPETING CONTINUATION	$399,509
														Subtotal = $399,509

Issue Date FY: 2018 ( Subtotal = $399,509 )
2018	2018	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	001	16	6/15/2018	NON-COMPETING CONTINUATION	$39,952
2018	2018	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	16	1/12/2018	NON-COMPETING CONTINUATION	$359,557
														Subtotal = $399,509

Issue Date FY: 2017 ( Subtotal = $423,296 )
2017	2017	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	002	15	8/8/2017	NON-COMPETING CONTINUATION	$42,598
2017	2017	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	15	1/24/2017	NON-COMPETING CONTINUATION	$383,374
2017	2013	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	HHS Programs for Disaster Relief Appropriations Act - Non Construction	001	13	6/6/2017	SUPPLEMENT FOR EXPANSION	-$2,676
														Subtotal = $423,296

Issue Date FY: 2016 ( Subtotal = $443,347 )
2016	2016	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	14	2/25/2016	COMPETING CONTINUATION	$443,347
														Subtotal = $443,347

Issue Date FY: 2013 ( Subtotal = $338,137 )
2013	2013	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	HHS Programs for Disaster Relief Appropriations Act - Non Construction	002	13	8/29/2013	SUPPLEMENT FOR EXPANSION	$338,137
2013	2012	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	13	7/29/2013	NON-COMPETING CONTINUATION	$0
2013	2012	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	001	13	8/29/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $338,137

Issue Date FY: 2012 ( Subtotal = $339,557 )
2012	2012	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	13	6/29/2012	NON-COMPETING CONTINUATION	$339,557
														Subtotal = $339,557

Issue Date FY: 2011 ( Subtotal = $339,557 )
2011	2011	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	12	9/8/2011	NON-COMPETING CONTINUATION	$339,557
														Subtotal = $339,557

Issue Date FY: 2010 ( Subtotal = $413,173 )
2010	2010	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	10	1/18/2010	SUPPLEMENT FOR EXPANSION	$35,270
2010	2010	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	001	11	6/28/2010	NON-COMPETING CONTINUATION	$377,903
														Subtotal = $413,173

Issue Date FY: 2009 ( Subtotal = $346,450 )
2009	2009	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	10	8/19/2009	COMPETING CONTINUATION	$346,450
														Subtotal = $346,450

Issue Date FY: 2007 ( Subtotal = $304,461 )
2007	2007	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	9	4/11/2007	NON-COMPETING CONTINUATION	$304,461
														Subtotal = $304,461

Issue Date FY: 2006 ( Subtotal = $313,554 )
2006	2006	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	8	4/24/2006	NON-COMPETING CONTINUATION	$313,554
														Subtotal = $313,554

Issue Date FY: 2005 ( Subtotal = $321,100 )
2005	2005	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	7	4/14/2005	NON-COMPETING CONTINUATION	$321,100
														Subtotal = $321,100

Issue Date FY: 2004 ( Subtotal = $321,100 )
2004	2004	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	6	4/15/2004	COMPETING CONTINUATION	$321,100
														Subtotal = $321,100

Issue Date FY: 2003 ( Subtotal = $330,667 )
2003	2003	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Genetics and Developmental Biology Research and Research Training	000	5		NON-COMPETING CONTINUATION	$330,667
														Subtotal = $330,667

Issue Date FY: 2002 ( Subtotal = $322,681 ) (Continued on the next page)
Grand Total All Awards = $7,864,371

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Control of Translation in Herpesvirus Infected Cells - Resubmission - 1

Award Number: R01GM056927

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: 05/01/1999

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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