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Regulation of the epithelial Ca2+ channels TRPV6 and TRPV5

Award Number: R01GM093290
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: 04/01/2011
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Regulation of the epithelial Ca2+ channels TRPV6 and TRPV5 - ABSTRACT Transient Receptor Vanilloid 6 (TRPV6) and its close relative TRPV5 are Ca2+ selective epithelial ion channels. The membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is the endogenous ligand of these channels that is required for their activity. These channels also undergo Ca2+-induced inactivation which is mediated by binding of Ca2+-calmodulin (CaM) to the channel. TRPV6 and TRPV5 are constitutively active, and their level of activity is determined by the balance between the activating PI(4,5)P2 and the inhibitory CaM. In the previous funding period, we identified the PI(4,5)P2 binding site in TRPV6 using homology modeling and site directed mutagenesis, which was essentially identical to the experimentally determined PI(4,5)P2 binding site in the closely related TRPV5. CryoEM structures for CaM and TRPV6 or TRPV5 also became available, showing a highly consistent picture of one CaM molecule binding to the channel tetramer, and blocking the pore in a fashion consistent with our experimental results. An important development during the previous funding period was the finding that loss of function mutations in TRPV6 are associated with chronic pancreatitis. The likely mechanism is reduced Ca2+ removal from pancreatic fluid in the acini or the ducts leading to increased Ca2+ and premature activation of pancreatic digestive enzymes. Given the crucial role of Ca2+ in digestive enzyme activation, small molecules that increase the activity of TRPV6 can, in principle, be used as novel therapeutic approach to treat pancreatitis. The overall goal of this application is to gain molecular insight into how the two key endogenous regulators PI(4,5)P2 and CaM gate TRPV6 and to use our molecular level understanding of their regulation to identify small molecules that increase their activity. We will use a combination of computational and experimental approaches to decipher the molecular mechanism of PI(4,5)P2 activation of TRPV6 and TRPV5 in Aim1, to determine the relationship between CaM and PI(4,5)P2 regulation of TRPV6 in Aim 2, and to identify small molecules that increase TRPV6 and/or TRPV5 activity by interfering with CaM inhibition in Aim 3. This work will further our understanding of TRPV6 and TRPV5 gating, and small molecules that enhance the activity of TRPV6 or TRPV5 can be used in future experiments to explore the possibility of using this approach to treat or prevent pancreatitis and kidney stones.


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 = $444,332 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	000	13	7/11/2025	NON-COMPETING CONTINUATION	$444,332
														Subtotal = $444,332

Issue Date FY: 2024 ( Subtotal = $475,261 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	000	12	6/18/2024	NON-COMPETING CONTINUATION	$475,261
														Subtotal = $475,261

Issue Date FY: 2023 ( Subtotal = $566,098 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	001	10	6/2/2023	SUPPLEMENT FOR EXPANSION	$81,578
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	002	11	6/7/2023	NON-COMPETING CONTINUATION	$484,520
2023	2020	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Biomedical Research and Research Training	000	9	1/23/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $566,098

Issue Date FY: 2022 ( Subtotal = $459,853 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	002	10	8/4/2022	COMPETING CONTINUATION	$459,853
2022	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Biomedical Research and Research Training	000	9	1/11/2022	NON-COMPETING CONTINUATION	$0
2022	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Biomedical Research and Research Training	001	9	7/27/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $459,853

Issue Date FY: 2020 ( Subtotal = $402,109 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Biomedical Research and Research Training	001	9	3/6/2020	NON-COMPETING CONTINUATION	$40,212
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Biomedical Research and Research Training	000	9	1/29/2020	NON-COMPETING CONTINUATION	$361,897
														Subtotal = $402,109

Issue Date FY: 2019 ( Subtotal = $402,109 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Biomedical Research and Research Training	000	8	1/18/2019	NON-COMPETING CONTINUATION	$402,109
														Subtotal = $402,109

Issue Date FY: 2018 ( Subtotal = $402,109 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Biomedical Research and Research Training	002	7	5/15/2018	NON-COMPETING CONTINUATION	$40,212
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Biomedical Research and Research Training	001	7	2/1/2018	NON-COMPETING CONTINUATION	$361,897
2018	2014	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Biomedical Research and Research Training	000	5	1/26/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $402,109

Issue Date FY: 2017 ( Subtotal = $416,859 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Biomedical Research and Research Training	001	6	1/16/2017	COMPETING CONTINUATION	$416,859
2017	2016	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Biomedical Research and Research Training	000	5	1/13/2017	SUPPLEMENT FOR EXPANSION	$0
2017	2014	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Biomedical Research and Research Training	002	5	1/17/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $416,859

Issue Date FY: 2016 ( Subtotal = $100,699 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	001	5	6/29/2016	SUPPLEMENT FOR EXPANSION	$100,699
2016	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	PISCATAWAY	NJ	088545602	MIDDLESEX	USA	Biomedical Research and Research Training	000	5	5/4/2016	NON-COMPETING CONTINUATION	$0
2016	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	PISCATAWAY	NJ	088545602	MIDDLESEX	USA	Biomedical Research and Research Training	002	5	6/30/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $100,699

Issue Date FY: 2014 ( Subtotal = $305,910 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	002	5	3/31/2014	NON-COMPETING CONTINUATION	$302,100
2014	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	001	4	1/6/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$201,976
2014	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	000	3	1/3/2014	NON-COMPETING CONTINUATION	-$198,166
														Subtotal = $305,910

Issue Date FY: 2013 ( Subtotal = $289,836 )
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	001	3	6/10/2013	NON-COMPETING CONTINUATION	$19,266
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	000	3	3/11/2013	NON-COMPETING CONTINUATION	$266,760
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Biomedical Research and Research Training	003	4	1/6/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$201,976
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	002	3	1/3/2014	NON-COMPETING CONTINUATION	-$198,166
														Subtotal = $289,836

Issue Date FY: 2012 ( Subtotal = $296,400 )
2012	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	000	2	4/2/2012	NON-COMPETING CONTINUATION	$296,400
														Subtotal = $296,400

Issue Date FY: 2011 ( Subtotal = $296,400 )
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	000	1	3/18/2011	NEW	$296,400
														Subtotal = $296,400

Grand Total All Awards = $4,857,975

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Regulation of the epithelial Ca2+ channels TRPV6 and TRPV5

Award Number: R01GM093290

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: 04/01/2011

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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