Wednesday, December 4, 2024 12/4/2024

RNA-dependent RNA Polymerase

Award Number: R01AI045818
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract The RNA-dependent RNA polymerase (RdRp) drives viral evolution by mediating both genetic drift (mutation) and genetic/antigenic shift (recombination) of RNA viruses. RdRp speed and fidelity contribute to the rate of mutation and formation of the mutant swarm, a well-established determinant of viral fitness and pathogenesis. For more than two decades, we have used the RdRp from poliovirus (PV) as a model system to elucidate fundamental biochemical and biophysical principles governing speed and fidelity of nucleotide addition. A major conclusion of this work is that both speed and fidelity are controlled by the dynamics of a conserved array of amino acid residues in the active site. Importantly, these dynamics can be manipulated genetically or exploited pharmacologically, thus contributing to the creation of attenuated strains and antiviral agents. RNA recombination in PV occurs by a template-switching mechanism, a process in which the RdRp initiates elongation on one template (donor) but completes elongation on a different template (acceptor). PV RdRp is sufficient to catalyze template switching in vitro. However, the trigger(s) and mechanism of template switching remain largely unknown. Using a novel cell-based assay for PV RNA recombination, the Evans laboratory observed a direct correlation between RdRp infidelity and the frequency of RNA recombination. RdRp misincorporation frequency as a biochemical property governing template switching was not expected but motivated our foray into the study of RNA recombination. Over the past five years, we have established an experimental paradigm to elucidate the mechanism of RdRp-catalyzed RNA recombination, discover biochemical and biophysical properties and structural determinants of the RdRp governing RNA recombination, and reveal the biological consequences of perturbations to the mechanism and/or efficiency of RNA recombination. Here, we will utilize our experimental paradigm to achieve the following: (1) Link structural determinants of the RdRp to elementary steps and mechanisms of RNA recombination; (2) Investigate the impact of RNA modifications on elongation and recombination by the RdRp; and (3) Reveal the mechanism and biological function of forced-copy-choice RNA recombination.


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: 2024 ( Subtotal = $404,270 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	25	6/10/2024	NON-COMPETING CONTINUATION	$404,270
														Subtotal = $404,270

Issue Date FY: 2023 ( Subtotal = $404,270 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	24	6/28/2023	NON-COMPETING CONTINUATION	$404,270
														Subtotal = $404,270

Issue Date FY: 2022 ( Subtotal = $404,270 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	004	23	6/23/2022	NON-COMPETING CONTINUATION	$404,270
2022	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	003	22	1/10/2022	COMPETING CONTINUATION	$21
2022	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	001	21	12/6/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$21
2022	2010	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Trans-NIH Recovery Act Research Support	000	11	12/6/2021	SUPPLEMENT FOR EXPANSION	$21
2022	2010	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Trans-NIH Recovery Act Research Support	002	11	1/10/2022	SUPPLEMENT FOR EXPANSION	-$21
														Subtotal = $404,270

Issue Date FY: 2021 ( Subtotal = $469,982 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	002	22	6/15/2021	COMPETING CONTINUATION	$469,982
2021	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	001	21	6/15/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	21	3/29/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $469,982

Issue Date FY: 2020 ( Subtotal = $23,254 )
2020	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	003	20	5/5/2020	NON-COMPETING CONTINUATION	-$47,400
2020	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	001	20	4/13/2020	NON-COMPETING CONTINUATION	-$288,583
2020	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	004	21	5/5/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$242,673
2020	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	21	4/10/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$311,837
2020	2018	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	002	19	5/5/2020	NON-COMPETING CONTINUATION	-$195,273
														Subtotal = $23,254

Issue Date FY: 2019 ( Subtotal = $335,983 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	20	3/29/2019	NON-COMPETING CONTINUATION	$335,983
														Subtotal = $335,983

Issue Date FY: 2018 ( Subtotal = $385,001 )
2018	2018	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	001	19	8/31/2018	NON-COMPETING CONTINUATION	$23,900
2018	2018	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	19	4/5/2018	NON-COMPETING CONTINUATION	$361,101
														Subtotal = $385,001

Issue Date FY: 2017 ( Subtotal = $361,216 )
2017	2017	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	18	4/10/2017	NON-COMPETING CONTINUATION	$361,216
														Subtotal = $361,216

Issue Date FY: 2016 ( Subtotal = $363,491 )
2016	2016	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	17	4/25/2016	NON-COMPETING CONTINUATION	$363,491
														Subtotal = $363,491

Issue Date FY: 2015 ( Subtotal = $371,943 )
2015	2015	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	001	16	4/27/2015	COMPETING CONTINUATION	$371,943
2015	2013	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	15	4/24/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $371,943

Issue Date FY: 2013 ( Subtotal = $272,703 )
2013	2013	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	15	6/13/2013	NON-COMPETING CONTINUATION	$272,703
														Subtotal = $272,703

Issue Date FY: 2012 ( Subtotal = $290,110 )
2012	2012	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	14	6/11/2012	NON-COMPETING CONTINUATION	$290,110
														Subtotal = $290,110

Issue Date FY: 2011 ( Subtotal = $333,894 )
2011	2011	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	13	7/1/2011	NON-COMPETING CONTINUATION	$333,894
														Subtotal = $333,894

Issue Date FY: 2010 ( Subtotal = $399,611 )
2010	2010	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	002	12	6/10/2010	NON-COMPETING CONTINUATION	$375,784
2010	2010	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	11	4/23/2010	SUPPLEMENT FOR EXPANSION	$8,044
2010	2010	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Trans-NIH Recovery Act Research Support	001	11	5/24/2010	SUPPLEMENT FOR EXPANSION	$15,783
														Subtotal = $399,611

Issue Date FY: 2009 ( Subtotal = $343,120 )
2009	2009	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	11	6/8/2009	COMPETING CONTINUATION	$343,120
														Subtotal = $343,120

Issue Date FY: 2008 ( Subtotal = $228,898 )
2008	2008	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	10	6/12/2008	NON-COMPETING CONTINUATION	$228,898
														Subtotal = $228,898

Issue Date FY: 2007 ( Subtotal = $233,841 )
2007	2007	PENNSYLVANIA STATE UNIVERSITY	313 RIDER BUILDING	UNIVERSITY PARK	PA	16801		USA	Allergy and Infectious Diseases Research	000	9	6/18/2007	NON-COMPETING CONTINUATION	$233,841
														Subtotal = $233,841

Issue Date FY: 2006 ( Subtotal = $241,303 )
2006	2006	PENNSYLVANIA STATE UNIVERSITY	313 RIDER BUILDING	UNIVERSITY PARK	PA	16801		USA	Allergy and Infectious Diseases Research	000	8	6/15/2006	NON-COMPETING CONTINUATION	$241,303
														Subtotal = $241,303

Grand Total All Awards = $7,297,272

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RNA-dependent RNA Polymerase

Award Number: R01AI045818

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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