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ANGLL AND PPARY/LXR IN ATHEROSCLEROSIS

Award Number: R01HL075171
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2005
PERIOD OF PERFORMANCE END DATE: 02/29/2008

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ANGLL AND PPARY/LXR IN ATHEROSCLEROSIS - DESCRIPTION (provided by applicant): Angiotensin II (Angll) is an important cardiovascular risk factor as evidenced by clinical trials demonstrating decreased events and mortality associated with drugs targeting the renin-angiotensin system (RAS), in which cardiovascular protection occurred independent of blood pressure lowering. In atherosclerosis-prone mice, Angll markedly accelerates complex lesion formation, which resembles advanced plaques in humans. However, the mechanism(s) by which Angll promotes more aggressive and advanced atherosclerosis in vivo is unknown. Exciting new data from our laboratory suggests that Angll suppresses expression of ABCA1, a key protein responsible for removal of cholesterol from foam cells (i.e. reverse cholesterol transport) that protects against atherosclerosis. We also find that ligands for the nuclear receptor peroxisome proliferator activated receptor-gamma (PPARgamma), currently used for the treatment of type 2 diabetes, substantially attenuate Angll-accelerated atherosclerosis in mice. PPARgamma, ligands have well described anti-inflammatory activity which likely contributes to their activity to inhibit atherosclerosis. Recently, PPARgamma ligands have been shown to increase macrophage levels of the liver X receptor alpha (LXRalpha) a major transcription factor up regulating ABCA1 expression. Studies designed to elucidate the competing vascular effects of Angll with PPARgamma/LXRalpha may yield new mechanistic insights leading to the design of new nuclear receptor drugs with greater cardiovascular efficacy. In this application, we hypothesize that down regulation of ABCA1 contributes to Angll-accelerated atherosclerosis and that preservation of macrophage ABCA1 by PPARgamma, and/or LXRalpha ligands may prevent the development of and/or promote the regression of atherosclerotic lesions. Specific Aims to test this hypothesis are: 1) Determine the mechanisms by which Angfl represses ABCA 1 transcription and the ability of PPARgamma ligands to reverse this process. 2) Determine whether PPARgamma Iigands reverse Angll suppression of ABCA 1 and its ultimate effect on atherosclerosis in Angll accelerated models with and without monocytes null for PPAR? and null for LXRalpha. 3) Determine the role of Fra 2 in ABCA1 regulation and atherosclerosis by developing transgenic mice overexpressing either wild-type or dominant-negative Fra 2 in monocytes/macrophages. 4) Determine whether PPARgamma ligands or LXRaalpha ligands can induce regression of established 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: 2008 ( Subtotal = $366,235 )
2008	2008	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	2/13/2008	NON-COMPETING CONTINUATION	$81,469
2008	2008	METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN WP 802	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	5	8/22/2008	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$284,766
														Subtotal = $366,235

Issue Date FY: 2007 ( Subtotal = $366,235 )
2007	2007	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	3	3/9/2007	NON-COMPETING CONTINUATION	$366,235
														Subtotal = $366,235

Issue Date FY: 2006 ( Subtotal = $377,173 )
2006	2006	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	1/30/2006	NON-COMPETING CONTINUATION	$377,173
														Subtotal = $377,173

Issue Date FY: 2005 ( Subtotal = $385,417 )
2005	2005	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	2/14/2005	NEW	$385,417
														Subtotal = $385,417

Grand Total All Awards = $1,495,060

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ANGLL AND PPARY/LXR IN ATHEROSCLEROSIS

Award Number: R01HL075171

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2005

PERIOD OF PERFORMANCE END DATE: 02/29/2008

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