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CERAMIDE AND CARDIOVASCULAR RISK IN OBESITY

Award Number: R01HL071146
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2004
PERIOD OF PERFORMANCE END DATE: 06/30/2009

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CERAMIDE AND CARDIOVASCULAR RISK IN OBESITY - DESCRIPTION (provided by applicant): Obesity is reaching epidemic proportions in western societies and over 65% of the adult U.S. population is either overweight or obese and will likely suffer clinical cardiovascular complications in the years ahead. In order to develop rational therapeutic approaches to treat the cardiovascular conditions attributable to obesity we need to first develop a comprehensive understanding of the molecular mechanisms of obesity-associated cardiovascular risk. Recent studies have documented the importance of the lipid second messenger, ceramide, in a variety of disorders including obesity, diabetes and atherosclerosis. The overall goal of this proposal is to use the pro-thrombotic cardiovascular risk gene, plasminogen activator inhibitor-1 (PAl-l), as a read out, to evaluate the role played by ceramide in the cardiovascular risk associated with obesity. In Aim 1 we will initially test the hypothesis that the levels of ceramide itself are elevated in adipose tissues in obesity, and that the hyperinsulinemia and elevated TNF-alpha associated with obesity contribute to this increase. In Aim 2, we will use PAl-1 as a read-out to test the hypothesis that ceramide and/or its bioactive metabolites, sphingosine and sphingosine-l-phosphate, are important regulators of cardiovascular risk in obesity, and that this pathway also contributes to obesity-associated increase in PAl-1 mediated by insulin and TNF-alpha. We also will determine signaling mechanisms that link ceramide to PAl-1 expression in the adipocyte. Finally, in Aim 3, we will test the hypothesis that membrane-bound TNF-alpha in the adipose tissue/adipocytes is an important mediator of increased ceramide and PAl-1 in obesity. These studies will not only advance our understanding of the molecular mechanisms that contribute to the induction of PAl-l, a gene that is consistently up regulated in obesity and positively correlated with cardiovascular risk, but will be clinically significant as they may directly identify novel pathways that link obesity to increased cardiovascular risk.


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: 2008 ( Subtotal = $388,286 )
2008	2008	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	000	6	7/9/2008	NON-COMPETING CONTINUATION	$388,286
														Subtotal = $388,286

Issue Date FY: 2007 ( Subtotal = $388,286 )
2007	2007	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	000	5	6/20/2007	NON-COMPETING CONTINUATION	$388,286
														Subtotal = $388,286

Issue Date FY: 2006 ( Subtotal = $455,468 )
2006	2006	LA JOLLA INSTITUTE FOR MOLECULAR MEDICINE	4570 EXECUTIVE DR, SUITE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	000	3	5/24/2006	NON-COMPETING CONTINUATION	$455,468
														Subtotal = $455,468

Issue Date FY: 2005 ( Subtotal = $466,425 )
2005	2005	LA JOLLA INSTITUTE FOR MOLECULAR MEDICINE	4570 EXECUTIVE DR, SUITE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	000	2	5/11/2005	NON-COMPETING CONTINUATION	$466,425
														Subtotal = $466,425

Issue Date FY: 2004 ( Subtotal = $491,425 )
2004	2004	LA JOLLA INSTITUTE FOR MOLECULAR MEDICINE	4570 EXECUTIVE DR, SUITE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cardiovascular Diseases Research	000	1	7/1/2004	NEW	$491,425
														Subtotal = $491,425

Grand Total All Awards = $2,189,890

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CERAMIDE AND CARDIOVASCULAR RISK IN OBESITY

Award Number: R01HL071146

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2004

PERIOD OF PERFORMANCE END DATE: 06/30/2009

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