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Mechanism of Viral Genome Delivery into Cells

Award Number: R35GM140733
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: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Mechanism of Viral Genome Delivery into Cells - Project Summary Nearly 120 years since the discovery of the first virus, our understanding of how viruses deliver genomes into cells overcoming the complexity of biological membranes remains limited. While a vast scientific literature exists on viral surface proteins and their interaction with host receptors, and the immune system, little emphasis has been devoted to studying the delivery of entire viral genomes into cells. For instance, how do bacteriophages eject DNA through the cell envelope of Gram-negative bacteria? Or, in humans, how do herpesviruses deliver ~200 kb genome through the Nuclear Pore Complex (NPC) into the cell nucleus? For a quarter of a century, first as a trainee (1995-2003), and since 2004 as a principal investigator, I have investigated the mechanisms of nucleocytoplasmic transport and viral genome packaging. My work has resulted in close to 85 publications that contributed to elucidating the atomic structure and regulation of crucial factors implicated in nuclear import, and viral genome packaging. In this R35, I propose to combine the study of these two seemingly distinct biological processes by focusing on the mechanisms of viral genome delivery into living cells. Specifically, I will ask two biological questions that seek to compare and contrast how simple bacterial viruses (or bacteriophages) eject their DNA into bacteria with how Herpesviruses deliver their complex genomes into the nucleus of eukaryotic cells. The first question explores how bacteriophages eject ~45 kb genomes through the cell envelope of gram-negative bacteria. Long-thought to be a simple pressure-driven injection, this process uses a virus-encoded nanomachine, which we have begun to study in my laboratory. The second question explores how Herpesviruses deliver their large genome through the Nuclear Pore Complex (NPC) of human cells into the cell nucleus. This is a signal- and energy-mediated process that uses host importins and the GTPase Ran, exploiting the cellular transport machinery to promote entry of an exogenous genome into the nucleus. Overall, understanding how viruses transfer genetic information through biological membranes into cells and organelles is vital for deciphering the molecular mechanisms of virulence as well as the development of novel therapeutic approaches. The common denominator of this R35 lies in our interest in the structure and transport mechanisms of biological macromolecules. Our research approach marries established sciences like protein biochemistry and X-ray crystallography with the power of cryo-electron microscopy (cryo-EM) to visualize biological macromolecules in near-native conditions. We believe that this R35 MIRA funding mechanism will fuel the creative and diligent pursuit of answers to the questions we pose, permitting our research program to achieve significant advancements in structural biology.


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 = $548,856 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	007	6	7/22/2025	NON-COMPETING CONTINUATION	$548,856
2025	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	000	5	11/18/2024	NON-COMPETING CONTINUATION	$0
2025	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	004	3	1/20/2025	NON-COMPETING CONTINUATION	-$232,059
2025	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	005	3	1/20/2025	SUPPLEMENT FOR EXPANSION	-$24,047
2025	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	006	4	1/20/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$277,171
2025	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	002	2	1/20/2025	SUPPLEMENT FOR EXPANSION	-$2,836
2025	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	001	2	1/20/2025	NON-COMPETING CONTINUATION	-$15,885
2025	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	003	2	1/20/2025	SUPPLEMENT FOR EXPANSION	-$2,344
														Subtotal = $548,856

Issue Date FY: 2024 ( Subtotal = $523,247 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	003	5	7/19/2024	NON-COMPETING CONTINUATION	$548,856
2024	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	001	3	6/24/2024	SUPPLEMENT FOR EXPANSION	-$4,308
2024	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	6/21/2024	NON-COMPETING CONTINUATION	-$344,517
2024	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	002	4	6/24/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$323,216
														Subtotal = $523,247

Issue Date FY: 2023 ( Subtotal = $604,931 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	001	3	7/14/2023	SUPPLEMENT FOR EXPANSION	$28,355
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	7/6/2023	NON-COMPETING CONTINUATION	$576,576
														Subtotal = $604,931

Issue Date FY: 2022 ( Subtotal = $764,577 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	002	2	8/8/2022	SUPPLEMENT FOR EXPANSION	$56,708
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	003	2	9/15/2022	SUPPLEMENT FOR EXPANSION	$102,938
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	001	2	7/19/2022	NON-COMPETING CONTINUATION	$576,576
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	1/12/2022	SUPPLEMENT FOR EXPANSION	$28,355
														Subtotal = $764,577

Issue Date FY: 2021 ( Subtotal = $343,092 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	5/27/2021	NEW	$343,092
														Subtotal = $343,092

Grand Total All Awards = $2,784,703

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Mechanism of Viral Genome Delivery into Cells

Award Number: R35GM140733

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: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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