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Eicosanoids and Vascular Wall Remodeling

Award Number: R01HL064165
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2000
PERIOD OF PERFORMANCE END DATE: 03/31/2019

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Eicosanoids and Vascular Wall Remodeling - DESCRIPTION (provided by applicant): Inflammation, in excess, was believed to be an underlying factor in the pathogenesis of proliferative cardiovascular diseases such as atherosclerosis. Phospholipase A2s (PLA2s) play an important role in inflammation. Arachidonic acid (AA), which is produced primarily by PLA2s, metabolizes via the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 monooxygenase (CYP) pathways producing prostaglandins (PGs), hydroperoxyeicosatetraenoic acids (HPETEs) and epoxyeicosatrienoic acids (EETs), respectively. While some of the COX and LOX products of AA are pro-inflammatory, CYP, particularly CYP2C8/9 products of AA, are anti-inflammatory. Atherosclerotic arteries produce 15(S)-HETE as a major 15- LOX product of AA. Although the involvement of 15-LOX1 in the oxidation of low-density lipoprotein has been extensively studied in understanding its role in the pathobiology of atherosclerosis, very little is known in regard to its AA product, 15(S)-HETE, in atherosclerosis. In this regard, during the previous funding cycle of this grant application, we have shown that 15(S)-HETE via inducing the expression of monocyte chemotactic protein-1 and interleukin-6 stimulates the migration of vascular smooth muscle cells, an important factor in vascular wall diseases. During the course of these studies, we also discovered that 15(S)-HETE stimulates macrophage migration. In addition, we observed that it activates Pyk2 and Syk, two non-receptor tyrosine kinases, and induces the expression of tissue factor, a clotting factor, and all of these molecules are involved in the mediation of inflammation. Based on these novel observations, we predict that eicosanoids, particularly the 15- LOX1/2 product of AA, 15(S)-HETE, via its capacity to trigger the migration and adhesion of macrophages to the aorta/artery under the influence of cardiovascular risk factors may set the soil for the development of atherosclerosis. To address this hypothesis, we have proposed to test the following specific aims: Aim 1: 15- LOX-15(S)-HETE via activating Pyk2 and Syk, two non-receptor tyrosine kinases, plays a key role in the stimulation of THP1 cell migration. Aim 2: 15-LOX-15(S)-HETE-induced THP1 cell migration requires TF expression and secretion. Aim 3: 12/15-LOX activity is required for stimulus-induced vascular inflammation. Thus, the experiments proposed in this grant application will provide novel information in regard to the potential role of 15-LOX-15(S)-HETE axis in macrophage recruitment and its adhesion to the aorta/artery leading to inflammation and development of atherosclerosis. Such knowledge would be useful in the development of therapeutic drugs against vascular diseases such as atherosclerosis.


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: 2019 ( Subtotal = -$8,005 )
2019	2016	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	18	7/17/2019	EXTENSION WITH OR WITHOUT FUNDS	-$8,005
														Subtotal = -$8,005

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	18	3/21/2018	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	18	3/26/2016	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	17	3/5/2015	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	16	3/5/2014	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	15	6/28/2013	NON-COMPETING CONTINUATION	$19,500
2013	2013	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	15	4/2/2013	NON-COMPETING CONTINUATION	$337,500
														Subtotal = $357,000

Issue Date FY: 2012 ( Subtotal = $349,750 )
2012	2012	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	14	4/2/2012	COMPETING CONTINUATION	$349,750
														Subtotal = $349,750

Issue Date FY: 2011 ( Subtotal = $365,000 )
2011	2011	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	13	3/15/2011	NON-COMPETING CONTINUATION	$365,000
														Subtotal = $365,000

Issue Date FY: 2010 ( Subtotal = $365,000 )
2010	2010	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	12	3/23/2010	NON-COMPETING CONTINUATION	$365,000
														Subtotal = $365,000

Issue Date FY: 2009 ( Subtotal = $365,000 )
2009	2009	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	004	11	9/16/2009	NON-COMPETING CONTINUATION	$365,000
2009	2009	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	002	11	4/6/2009	NON-COMPETING CONTINUATION	$365,000
2009	2009	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	003	11	9/14/2009	NON-COMPETING CONTINUATION	-$365,000
2009	2008	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	001	10	9/23/2009	COMPETING CONTINUATION	$342,000
2009	2008	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	10	9/17/2009	COMPETING CONTINUATION	-$342,000
														Subtotal = $365,000

Issue Date FY: 2008 ( Subtotal = $342,000 )
2008	2008	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	000	10	1/21/2008	COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2007 ( Subtotal = $276,869 )
2007	2007	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	9	3/21/2007	NON-COMPETING CONTINUATION	$276,869
														Subtotal = $276,869

Issue Date FY: 2006 ( Subtotal = $285,138 )
2006	2006	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	8	3/28/2006	NON-COMPETING CONTINUATION	$285,138
														Subtotal = $285,138

Issue Date FY: 2005 ( Subtotal = $292,000 )
2005	2005	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	7	3/28/2005	NON-COMPETING CONTINUATION	$292,000
														Subtotal = $292,000

Issue Date FY: 2004 ( Subtotal = $342,000 )
2004	2004	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	6	3/25/2004	COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2003 ( Subtotal = $234,064 )
2003	2003	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	5		NON-COMPETING CONTINUATION	$234,064
														Subtotal = $234,064

Issue Date FY: 2002 ( Subtotal = $227,247 )
2002	2002	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	4	1/25/2002	NON-COMPETING CONTINUATION	$227,247
														Subtotal = $227,247

Issue Date FY: 2001 ( Subtotal = $220,629 )
2001	2001	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Cardiovascular Diseases Research	000	3	1/31/2001	NON-COMPETING CONTINUATION	$220,629
														Subtotal = $220,629

Issue Date FY: 2000 ( Subtotal = $226,202 )
2000	2000	UNIVERSITY OF TEXAS, MEDICAL BRANCH AT GALVESTON	1000 STRAND	GALVESTON	TX	77550	GALVESTON	USA	Cardiovascular Diseases Research	000	1	1/24/2000	NEW	$226,202
														Subtotal = $226,202

Grand Total All Awards = $5,351,769

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Eicosanoids and Vascular Wall Remodeling

Award Number: R01HL064165

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2000

PERIOD OF PERFORMANCE END DATE: 03/31/2019

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