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Vascular control by K+ channel trafficking

Award Number: R01HL067061
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2002
PERIOD OF PERFORMANCE END DATE: 10/31/2018

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Vascular control by K+ channel trafficking - DESCRIPTION (provided by applicant): Small (resistance-size) cerebral arteries and arterioles control regional brain blood flow, thereby providing neurons and other brain cells with necessary oxygen and nutrients. An essential regulator of artery contractility is smooth muscle cell membrane potential, which is controlled by ion channels. Hypertension is associated with increased risk for cerebral diseases, including stroke and dementia. Cerebral arteries from hypertensive subjects are depolarized, leading to elevated contractility, but mechanisms involved in this pathological alteration are unclear. Previous studies have focused on identifying mechanisms that regulate the activity of ion channels located in the plasma membrane of arterial smooth muscle cells. In contrast, mechanisms that control the number of functional ion channels and their auxiliary subunits in the plasma membrane of smooth muscle cells are unclear. Large-conductance calcium (Ca2+)-activated potassium (BKCa) channels are a major physiological modulator of arterial smooth muscle cell membrane potential and contractility. Arterial smooth muscle cells express two BKCa channel subunits: a pore-forming ¿(BK¿) and an auxiliary ¿1 that is essential for channel physiological functions. This application stems from novel preliminary data indicating that physiological stimuli control BK¿ and ¿1 surface expression to modulate channel subunit composition, channel activity and arterial contractility. We also provide evidence that hypertension is associated with pathological alterations in mechanisms that regulate BKCa channel subunit surface expression, thereby promoting vasoconstriction. Three specific aims will be investigated to test the central hypothesis that vasoregulatory stimuli modulate surface expression of BKCa channel subunits to control cerebral artery contractility, and that pathological modification of these processes leads to vasoconstriction associated with cerebrovascular disease. Aim 1 will examine the hypothesis that vasodilators and vasoconstrictors regulate ¿1 subunit surface expression to control BKCa channel activity in smooth muscle cells and arterial contractility. Aim 2 will investigate the hypothesis that vasoconstrictors and vasodilators modulate BK¿ surface expression and degradation to regulate smooth muscle cell BKCa channel activity and arterial contractility. Aim 3 will explore the hypothesis that hypertension is associated with dysfunctional control of BK¿ and ¿1 subunit surface expression that stimulates vasoconstriction. Methods used to test these hypotheses will include arterial biotinylation, FRET, RNAi, co-IP, immunofluorescence, patch-clamp electrophysiology, membrane potential recording, intracellular Ca2+ imaging and arterial myography. This proposal will provide significant novel information concerning cerebral artery contractility regulation by physiological and pathological mechanisms that control BKCa channel surface expression.


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: 2020 ( Subtotal = -$5 )
2020	2016	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	14	1/28/2020	EXTENSION WITH OR WITHOUT FUNDS	-$5
														Subtotal = -$5

Issue Date FY: 2019 ( Subtotal = -$40,107 )
2019	2016	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	001	14	2/15/2019	EXTENSION WITH OR WITHOUT FUNDS	-$40,107
2019	2016	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	14	10/27/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = -$40,107

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	14	5/11/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $375,000 )
2016	2016	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	14	4/1/2016	EXTENSION WITH OR WITHOUT FUNDS	$375,000
														Subtotal = $375,000

Issue Date FY: 2015 ( Subtotal = $369,375 )
2015	2015	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	13	5/5/2015	NON-COMPETING CONTINUATION	$369,375
														Subtotal = $369,375

Issue Date FY: 2014 ( Subtotal = $367,500 )
2014	2014	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	12	4/28/2014	NON-COMPETING CONTINUATION	$367,500
														Subtotal = $367,500

Issue Date FY: 2013 ( Subtotal = $357,000 )
2013	2013	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	001	11	8/1/2013	COMPETING CONTINUATION	$357,000
2013	2012	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	10	7/30/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $357,000

Issue Date FY: 2012 ( Subtotal = $325,215 )
2012	2012	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	10	3/30/2012	NON-COMPETING CONTINUATION	$325,215
														Subtotal = $325,215

Issue Date FY: 2011 ( Subtotal = $409,388 )
2011	2011	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	9	3/7/2011	NON-COMPETING CONTINUATION	$409,388
														Subtotal = $409,388

Issue Date FY: 2010 ( Subtotal = $406,780 )
2010	2010	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	8	3/2/2010	NON-COMPETING CONTINUATION	$406,780
														Subtotal = $406,780

Issue Date FY: 2009 ( Subtotal = $402,272 )
2009	2009	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	002	7	9/15/2009	NON-COMPETING CONTINUATION	-$402,272
2009	2009	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	7	9/17/2009	NON-COMPETING CONTINUATION	$402,272
2009	2009	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	001	7	3/11/2009	NON-COMPETING CONTINUATION	$402,272
														Subtotal = $402,272

Issue Date FY: 2008 ( Subtotal = $398,631 )
2008	2008	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	000	6	3/28/2008	COMPETING CONTINUATION	$328,500
2008	2008	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	001	6	6/24/2008	SUPPLEMENT FOR EXPANSION	$70,131
														Subtotal = $398,631

Issue Date FY: 2006 ( Subtotal = $279,279 )
2006	2006	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	5	3/28/2006	NON-COMPETING CONTINUATION	$279,279
														Subtotal = $279,279

Issue Date FY: 2005 ( Subtotal = $286,000 )
2005	2005	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	4	2/15/2005	NON-COMPETING CONTINUATION	$286,000
														Subtotal = $286,000

Issue Date FY: 2004 ( Subtotal = $286,000 )
2004	2004	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	3	3/1/2004	NON-COMPETING CONTINUATION	$286,000
														Subtotal = $286,000

Issue Date FY: 2003 ( Subtotal = $286,000 )
2003	2003	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	2		NON-COMPETING CONTINUATION	$286,000
														Subtotal = $286,000

Issue Date FY: 2002 ( Subtotal = $286,000 )
2002	2002	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	1	3/25/2002	NEW	$286,000
														Subtotal = $286,000

Grand Total All Awards = $4,794,328

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Vascular control by K+ channel trafficking

Award Number: R01HL067061

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2002

PERIOD OF PERFORMANCE END DATE: 10/31/2018

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