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High-resolution insights into insecticide interactions with voltage-gated sodium channels

Award Number: R01GM057440
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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High-resolution insights into insecticide interactions with voltage-gated sodium channels - Project Summary Voltage-gated sodium channels (Navs) are targets of a variety of natural neurotoxins and insecticides, including pyrethroids and sodium-channel-blocker insecticides (SCBIs). Pyrethroids are currently one of the most important and effective arsenals against mosquitoes and other arthropod vectors that transmit human diseases. SCBIs belong to a newer class of selective insecticides. A major challenge for effective vector control is global emergence of insecticide resistance. In particular, mutations in Nav genes confer a major form of resistance known as knockdown resistance (kdr). In the absence of 3-D structures of eukaryotic Navs in complex with pyrethroids or SCBIs, major uncertainties remain in understanding their interactions (including the nature of respective receptor sites) and kdr mechanisms. In this grant proposal, we take advantage of recent breakthroughs in the co-PI’s laboratory in the determination of the cryo-EM structures of several eukaryotic Navs. The availability of these Nav structures now promises an unprecedented new level of understanding of Nav interactions with insecticides and other neurotoxins. We propose to determine cryo-EM structures of Navs in complex with pyrethroids, SCBIs and three other neurotoxins and use these structures as a guide to conduct a comprehensive series of mutational, electrophysiological and computational modeling analyses of respective Nav-ligand interactions. Two specific aims of this renewal proposal are: 1) determine cryo-EM structures of eukaryotic Nav complexes with various pyrethroids to gain insights into the atomic mechanisms of pyrethroids and kdr, and 2) Investigate the mechanisms of Nav interactions with SCBIs (DCJW and metaflumizone), steroidal agonists (BTX and veratridine) and the alkylamide insecticide BTG 502. Results from this research will push our understanding of the molecular actions of pyrethroids, SCBIs and other neurotoxins to a new level, thereby facilitating the development of precision monitoring and management of insecticide resistance worldwide and discovery of new and safe Nav-targeting chemicals to combat global threats from arthropod disease-transmitting vectors.


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: 2023 ( Subtotal = $377,037 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	001	21	4/13/2023	NON-COMPETING CONTINUATION	$377,037
2023	2022	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	20	2/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $377,037

Issue Date FY: 2022 ( Subtotal = $377,037 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	20	4/13/2022	NON-COMPETING CONTINUATION	$339,333
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	001	20	5/17/2022	NON-COMPETING CONTINUATION	$37,704
														Subtotal = $377,037

Issue Date FY: 2021 ( Subtotal = $394,394 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	004	19	4/26/2021	NON-COMPETING CONTINUATION	$377,037
2021	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	006	18	5/16/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$10,869
2021	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	003	18	1/14/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$195,640
2021	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	001	17	10/3/2020	COMPETING CONTINUATION	$6,875
2021	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	005	17	5/16/2021	COMPETING CONTINUATION	-$10,869
2021	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	002	17	1/13/2021	COMPETING CONTINUATION	-$178,283
2021	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	17	10/1/2020	COMPETING CONTINUATION	-$6,875
														Subtotal = $394,394

Issue Date FY: 2020 ( Subtotal = $386,924 )
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	001	17	5/13/2020	COMPETING CONTINUATION	$6,875
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	17	4/24/2020	COMPETING CONTINUATION	$380,049
														Subtotal = $386,924

Issue Date FY: 2018 ( Subtotal = -$6,875 )
2018	2015	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	16	1/25/2018	NON-COMPETING CONTINUATION	-$6,875
														Subtotal = -$6,875

Issue Date FY: 2015 ( Subtotal = $341,110 )
2015	2015	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	16	8/24/2015	NON-COMPETING CONTINUATION	$341,110
														Subtotal = $341,110

Issue Date FY: 2014 ( Subtotal = $341,512 )
2014	2014	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	15	8/27/2014	NON-COMPETING CONTINUATION	$341,512
														Subtotal = $341,512

Issue Date FY: 2013 ( Subtotal = $329,922 )
2013	2013	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	14	8/23/2013	NON-COMPETING CONTINUATION	$329,922
														Subtotal = $329,922

Issue Date FY: 2012 ( Subtotal = $355,614 )
2012	2012	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	13	8/3/2012	COMPETING CONTINUATION	$355,614
														Subtotal = $355,614

Issue Date FY: 2010 ( Subtotal = $280,139 )
2010	2010	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	12	2/22/2010	NON-COMPETING CONTINUATION	$280,139
														Subtotal = $280,139

Issue Date FY: 2009 ( Subtotal = $283,261 )
2009	2009	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	001	11	3/31/2009	NON-COMPETING CONTINUATION	$28,326
2009	2009	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	11	12/18/2008	NON-COMPETING CONTINUATION	$254,935
														Subtotal = $283,261

Issue Date FY: 2008 ( Subtotal = $283,530 )
2008	2008	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	10	2/25/2008	NON-COMPETING CONTINUATION	$283,530
														Subtotal = $283,530

Issue Date FY: 2007 ( Subtotal = $283,780 )
2007	2007	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	9	12/26/2006	COMPETING CONTINUATION	$283,780
														Subtotal = $283,780

Issue Date FY: 2006 ( Subtotal = $218,980 )
2006	2006	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	8	12/27/2005	NON-COMPETING CONTINUATION	$218,980
														Subtotal = $218,980

Issue Date FY: 2005 ( Subtotal = $224,250 )
2005	2005	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	7	12/20/2004	NON-COMPETING CONTINUATION	$224,250
														Subtotal = $224,250

Issue Date FY: 2004 ( Subtotal = $224,250 )
2004	2004	MICHIGAN STATE UNIVERSITY	ADMINISTRATION BLDG ROOM 302	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	6	12/17/2003	NON-COMPETING CONTINUATION	$224,250
														Subtotal = $224,250

Issue Date FY: 2003 ( Subtotal = $223,875 )
2003	2003	MICHIGAN STATE UNIVERSITY	ADMINISTRATION BLDG ROOM 302	EAST LANSING	MI	48824	INGHAM	USA	Cell Biology and Biophysics Research	000	5		COMPETING CONTINUATION	$223,875
														Subtotal = $223,875

Issue Date FY: 2002 ( Subtotal = $152,249 )
2002	2002	MICHIGAN STATE UNIVERSITY	ADMINISTRATION BLDG ROOM 302	EAST LANSING	MI	48824	INGHAM	USA	Cell Biology and Biophysics Research	000	4	12/24/2001	NON-COMPETING CONTINUATION	$152,249
														Subtotal = $152,249

Issue Date FY: 2001 ( Subtotal = $147,901 )
2001	2001	MICHIGAN STATE UNIVERSITY	ADMINISTRATION BLDG ROOM 302	EAST LANSING	MI	48824	INGHAM	USA	Cell Biology and Biophysics Research	000	3	1/1/2001	NON-COMPETING CONTINUATION	$147,901
														Subtotal = $147,901

Issue Date FY: 2000 ( Subtotal = $143,438 )
2000	2000	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Cell Biology and Biophysics Research	000	2	12/24/1999	NON-COMPETING CONTINUATION	$143,438
														Subtotal = $143,438

Grand Total All Awards = $5,501,201

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High-resolution insights into insecticide interactions with voltage-gated sodium channels

Award Number: R01GM057440

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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