Thursday, November 21, 2024 11/21/2024

Structure-function analysis of the volume-regulated anion channel VRAC using novel LRRC8 chimeras

Award Number: R01DK051610
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The volume-regulated anion channel (VRAC) is expressed ubiquitously in vertebrate cells where it mediates the efflux of Cl- and organic solutes required for cell volume regulation, an essential physiological process. VRACs are activated and inactivated by cell swelling and shrinkage, respectively. They also detect changes in intracellular ionic strength, which modifies their sensitivity to cell volume changes. VRACs and the genes that encode them are implicated in multiple diseases including diabetes, obesity, cancer and immunity. Whole genome RNA interference screening led to the demonstration in 2014 that VRACs are encoded by five members of the Lrrc8 gene family, Lrrc8a–e. VRAC/LRRC8 channels are hexaheteromers and require co-assembly of the essential subunit LRRC8A with one or more other LRRC8 proteins. Subunit assembly order and stoichiometry are unknown. Cryo-electron microscopy (EM) structures of homomeric LRRC8A and LRRC8D channels were recently determined. However, LRRC8A and LRRC8D homomers do not exist in Nature. Furthermore, LRRC8A homomeric channels have non-native functional properties and LRRC8D channel properties are undefinable because they are not trafficked to the plasma membrane. Existing cryo-EM structures thus have limitations for understanding VRAC/LRRC8 structure-function relationships. Directly translating LRRC8A and LRRC8D cryo-EM structural information into functional understanding is further constrained by the unknown and likely variable stoichiometry and assembly of hexaheteromeric VRAC/LRRC8 channels. Our laboratory, funded by DK51610, has studied VRAC extensively and was the first to demonstrate many of the channel's unique functional properties. Most recently, we described novel LRRC8 chimeric channel constructs that allow detailed molecular study of homomeric channels with physiologically relevant functional properties and defined stoichiometry and assembly. Our chimera studies uniquely demonstrated that 1) the LRRC8A intracellular loop, IL1, has unique structural features, 2) it is required for cell volume sensing, 3) the LRRC8 C-terminus is required for sensing changes in intracellular ionic strength and 4) both the LRRC8A IL1 and C-terminus are required for correct cellular processing of VRAC/LRRC8 channels. The overarching goal of this R01 renewal application is to utilize these novel LRRC8 chimeras to better elucidate VRAC/LRRC8 channel structure-function relationships. We will characterize the roles of the LRRC8A C-terminus in VRAC/LRRC8 channel regulation and will test the hypothesis that the LRRC8 IL1 determines VRAC/LRRC8 channel pore properties and regulates channel gating. We will also determine the cryo-EM structure of a unique LRRC8 chimera in multiple physiologically relevant conformations. Our studies will provide novel insights into the regulation and function of VRAC/LRRC8 channels and will provide a higher confidence foundation for detailed mutagenesis-based structure-function analyses.


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 = $0 )
2025	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	29	10/1/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $474,220 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	29	7/15/2024	NON-COMPETING CONTINUATION	$474,220
														Subtotal = $474,220

Issue Date FY: 2023 ( Subtotal = $493,978 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	28	6/21/2023	NON-COMPETING CONTINUATION	$493,978
														Subtotal = $493,978

Issue Date FY: 2022 ( Subtotal = $493,978 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	27	8/30/2022	NON-COMPETING CONTINUATION	$493,978
2022	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	26	11/25/2021	COMPETING CONTINUATION	$0
2022	2019	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	11/25/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $493,978

Issue Date FY: 2021 ( Subtotal = $512,228 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	26	8/20/2021	COMPETING CONTINUATION	$512,228
														Subtotal = $512,228

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	25	3/13/2020	NON-COMPETING CONTINUATION	$236,443
2020	2018	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	23	3/13/2020	NON-COMPETING CONTINUATION	-$85,308
2020	2017	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	3/13/2020	NON-COMPETING CONTINUATION	-$151,135
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $342,253 )
2019	2019	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	25	7/3/2019	NON-COMPETING CONTINUATION	$355,500
2019	2018	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	24	1/9/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$290,695
2019	2018	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	24	2/25/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2018	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	1/3/2019	NON-COMPETING CONTINUATION	-$303,942
														Subtotal = $342,253

Issue Date FY: 2018 ( Subtotal = $389,250 )
2018	2018	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	6/27/2018	NON-COMPETING CONTINUATION	$389,250
														Subtotal = $389,250

Issue Date FY: 2017 ( Subtotal = $387,336 )
2017	2017	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	22	7/11/2017	NON-COMPETING CONTINUATION	$392,463
2017	2012	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	4/7/2017	NON-COMPETING CONTINUATION	$0
2017	2012	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	19	9/30/2017	NON-COMPETING CONTINUATION	-$5,127
														Subtotal = $387,336

Issue Date FY: 2016 ( Subtotal = $392,463 )
2016	2016	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	**	SALISBURY COVE	ME	04672		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	6/30/2016	NON-COMPETING CONTINUATION	$392,463
														Subtotal = $392,463

Issue Date FY: 2015 ( Subtotal = $392,463 )
2015	2015	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	**	SALISBURY COVE	ME	04672		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	7/8/2015	COMPETING CONTINUATION	$392,463
														Subtotal = $392,463

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2012	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	**	SALISBURY COVE	ME	04672		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	7/8/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $375,464 )
2012	2012	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	Old Bar Harbor Road	SALISBURY COVE	ME	04672		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	6/28/2012	NON-COMPETING CONTINUATION	$375,464
														Subtotal = $375,464

Issue Date FY: 2011 ( Subtotal = $375,462 )
2011	2011	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	Old Bar Harbor Road	SALISBURY COVE	ME	04672		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	6/17/2011	NON-COMPETING CONTINUATION	$375,462
														Subtotal = $375,462

Issue Date FY: 2010 ( Subtotal = $457,957 )
2010	2010	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	Old Bar Harbor Road	SALISBURY COVE	ME	04672		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	17	7/12/2010	NON-COMPETING CONTINUATION	$418,490
2010	2009	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	Old Bar Harbor Road	SALISBURY COVE	ME	04672		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	16	2/26/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$310,152
2010	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	2/26/2010	COMPETING CONTINUATION	-$270,685
														Subtotal = $457,957

Issue Date FY: 2009 ( Subtotal = $358,179 )
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	7/23/2009	COMPETING CONTINUATION	$358,179
														Subtotal = $358,179

Issue Date FY: 2008 ( Subtotal = $345,841 )
2008	2008	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Kidney Diseases, Urology and Hematology Research	000	14	7/1/2008	NON-COMPETING CONTINUATION	$345,841
														Subtotal = $345,841

Issue Date FY: 2007 ( Subtotal = $342,619 )
2007	2007	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Kidney Diseases, Urology and Hematology Research	000	13	6/21/2007	NON-COMPETING CONTINUATION	$342,619
														Subtotal = $342,619

Issue Date FY: 2006 ( Subtotal = $342,574 )
2006	2006	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Kidney Diseases, Urology and Hematology Research	000	12	7/3/2006	NON-COMPETING CONTINUATION	$342,574
														Subtotal = $342,574

Issue Date FY: 2005 ( Subtotal = $417,379 ) (Continued on the next page)
Grand Total All Awards = $8,910,600

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Structure-function analysis of the volume-regulated anion channel VRAC using novel LRRC8 chimeras

Award Number: R01DK051610

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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