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Structural Studies of Ion Channel Assembly and Signaling Complexes

Award Number: R01DC007664
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract The long-term goals of this project are to develop a high-resolution understanding of ion channel function and regulation. Our studies focus on uncovering the architectural foundations that underlie the modulation of exemplar classes from the voltage-gated ion channel (VGIC) superfamily and seek to address the fundamental question of how conformational changes in channel intracellular domains control and shape VGIC function. Many VGIC superfamily members, including Kv7 voltage-gated potassium channels and BacNaV bacterial voltage-gated sodium channels, share a common cytoplasmic domain architecture in which the pore domain and a four-stranded coiled-coil frame a metastable membrane proximal domain that acts as a receiver for modulatory signals. We aim to understand how such metastable domains sense inputs from the calcium sensor calmodulin in Kv7s and from temperature in BacNaVs and transmit signals to the channel pore. The prevalence of similar intracellular elements among diverse VGICs suggests that the principles derived from these studies will have broad impact in defining how such intracellular modules shape channel responses. A second effort is directed at defining the architecture of a class of intracellular endolysosomal VGICs known as Two-Pore-Channels (TPCs) and that have limited structural characterization. These channels possess a unique tandem transmembrane architecture and respond to a variety of intracellular signals, including calcium. Elaboration of the underlying structural framework of exemplar VGICs is essential for understanding how these and other VGICs are integrated into intracellular signaling pathways and for developing novel ways to intervene to control channel function. Our efforts encompass a multidisciplinary approach that includes biochemical, biophysical, X-ray crystallographic, and cryo-electronmicroscopy studies to probe structure and electrophysiological measurements to dissect function. Because of their important role in human physiology, VGICs are the targets for drugs with great utility for the treatment of cardiac arrhythmias, hypertension, congestive heart failure, epilepsy, and chronic pain. Thus, understanding their structures and mechanisms of action at atomic level detail should greatly assist the development of valuable therapeutic agents for a wide range of human ailments.


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 = $685,689 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	16	3/5/2024	COMPETING CONTINUATION	$678,811
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	001	16	3/13/2024	COMPETING CONTINUATION	$6,878
														Subtotal = $685,689

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	15	1/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $487,507 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	15	1/16/2021	NON-COMPETING CONTINUATION	$487,507
														Subtotal = $487,507

Issue Date FY: 2020 ( Subtotal = $487,507 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	14	1/17/2020	NON-COMPETING CONTINUATION	$487,507
														Subtotal = $487,507

Issue Date FY: 2019 ( Subtotal = $487,507 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	13	1/10/2019	NON-COMPETING CONTINUATION	$487,507
														Subtotal = $487,507

Issue Date FY: 2018 ( Subtotal = $493,616 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	001	12	4/5/2018	NON-COMPETING CONTINUATION	$49,362
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	12	1/25/2018	NON-COMPETING CONTINUATION	$444,254
														Subtotal = $493,616

Issue Date FY: 2017 ( Subtotal = $543,723 )
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	003	11	5/18/2017	COMPETING CONTINUATION	$8,087
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	001	11	2/8/2017	COMPETING CONTINUATION	$543,723
2017	2015	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	002	10	5/18/2017	NON-COMPETING CONTINUATION	-$8,087
2017	2015	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	10	2/8/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $543,723

Issue Date FY: 2015 ( Subtotal = $325,029 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	10	1/15/2015	NON-COMPETING CONTINUATION	$325,029
														Subtotal = $325,029

Issue Date FY: 2014 ( Subtotal = $328,313 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	001	9	2/10/2014	NON-COMPETING CONTINUATION	$32,832
2014	2014	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	9	1/23/2014	NON-COMPETING CONTINUATION	$295,481
														Subtotal = $328,313

Issue Date FY: 2013 ( Subtotal = $311,897 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	001	8	5/14/2013	NON-COMPETING CONTINUATION	$16,416
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	8	1/15/2013	NON-COMPETING CONTINUATION	$295,481
														Subtotal = $311,897

Issue Date FY: 2012 ( Subtotal = $328,313 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	001	7	1/26/2012	NON-COMPETING CONTINUATION	$32,832
2012	2012	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	7	1/20/2012	NON-COMPETING CONTINUATION	$295,481
														Subtotal = $328,313

Issue Date FY: 2011 ( Subtotal = $328,313 )
2011	2011	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	6	2/15/2011	COMPETING CONTINUATION	$328,313
2011	2009	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	001	5	2/15/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $328,313

Issue Date FY: 2010 ( Subtotal = $100,000 )
2010	2010	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	5	7/20/2010	SUPPLEMENT FOR EXPANSION	$100,000
														Subtotal = $100,000

Issue Date FY: 2009 ( Subtotal = $354,454 )
2009	2009	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	5	6/18/2009	NON-COMPETING CONTINUATION	$354,454
														Subtotal = $354,454

Issue Date FY: 2008 ( Subtotal = $404,454 )
2008	2008	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	001	3	3/21/2008	SUPPLEMENT FOR EXPANSION	$50,000
2008	2008	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	4	6/13/2008	NON-COMPETING CONTINUATION	$354,454
														Subtotal = $404,454

Issue Date FY: 2007 ( Subtotal = $359,123 )
2007	2007	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	3	6/22/2007	NON-COMPETING CONTINUATION	$359,123
														Subtotal = $359,123

Issue Date FY: 2006 ( Subtotal = $369,849 )
2006	2006	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	2	6/16/2006	NON-COMPETING CONTINUATION	$369,849
														Subtotal = $369,849

Issue Date FY: 2005 ( Subtotal = $378,750 )
2005	2005	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research Related to Deafness and Communication Disorders	000	1	6/13/2005	NEW	$378,750
														Subtotal = $378,750

Grand Total All Awards = $6,774,044

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Structural Studies of Ion Channel Assembly and Signaling Complexes

Award Number: R01DC007664

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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