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AGING AND VASCULAR DISEASE: ROLE OF GLYCATION

Award Number: R01AG009453
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/1992
PERIOD OF PERFORMANCE END DATE: 04/30/2008

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AGING AND VASCULAR DISEASE: ROLE OF GLYCATION - DESCRIPTION (provided by applicant): Protein, and lipid-derived Advanced Glycoxidation Endproducts (AGE) have been linked to a spectrum of cellular oxidative responses leading to tissue injury via enhanced cytokine, growth factor, matrix production, vascular dysfunction, and atherogenesis. Vascular endothelial cells (EC) and other cells express a spectrum of AGE-binding proteins, some of which mediate endocytosis and clearance, but others trigger oxidant stress via ROS generation, and Nf-kB activation, contributing to inflammatory events, in a self perpetuating manner, which in the presence of diabetes, leads to accelerated atherogenesis. Based on presented evidence, we propose that in diabetes and/or aging normal AGE detoxification mechanisms are overwhelmed by marked increases in AGE burden, from exogenous and endogenous sources, and the resulting glycoxidant excess, together with other metabolites (glucose, lipids) leads to low-grade inflammatory state, underlying diabetes and diabetic vascular injury. The main goal of this Continuation proposal is to identify possible mechanisms by which environmental oxidant or carbonyl stress and systemic vascular toxicity can be balanced, either by enhancing AGE-receptor (AGER) mediated clearance or by inhibiting AGE-promoted inflammatory signaling cascades. This goal will be approached by assessing: Aim 1a: Early AGER signaling events of endocytotic pathways vs. Nf-kB activation pathways and of AGER-dependent negative or inhibitory cell activation pathways in endothelial cells or macrophages (Mf) over-expressing AGER1, R2, R3 and RAGE; 1b. Differences in AGER signaling in cells from aging mice, Aim 2a. Effects of environmental AGE stress on AGE-R clearance vs activation as a function of age in mice: in vitro studies, or 2b., in ApoE-deficient mice, a model of atherogenesis. Aim 3a: Effects of AGE-binding peptide, Lysozyme peptide (LZ-p) overexpression on AGER signaling, and 3b: In vivo effects of Lz-p on AGER-mediated clearance and tissue pathology in Lz-p transgenic mice, exposed to high AGE states, eg. diabetes, diet. The proposed studies will expand our understanding of this basic process and may allow us to identify ways to prevent AGE-induced vascular injury due to diabetes and aging.


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: 2007 ( Subtotal = $401,791 )
2007	2007	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	000	17	4/30/2007	NON-COMPETING CONTINUATION	$401,791
														Subtotal = $401,791

Issue Date FY: 2006 ( Subtotal = $413,792 )
2006	2006	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	000	16	4/28/2006	NON-COMPETING CONTINUATION	$413,792
														Subtotal = $413,792

Issue Date FY: 2005 ( Subtotal = $423,750 )
2005	2005	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	000	15	4/25/2005	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2004 ( Subtotal = $423,750 )
2004	2004	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	000	14	5/3/2004	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2003 ( Subtotal = $423,750 )
2003	2003	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	000	13		COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2001 ( Subtotal = $243,177 )
2001	2001	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	000	12	6/25/2001	NON-COMPETING CONTINUATION	$243,177
														Subtotal = $243,177

Issue Date FY: 2000 ( Subtotal = $237,515 )
2000	2000	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	000	11	7/24/2000	NON-COMPETING CONTINUATION	$237,515
														Subtotal = $237,515

Issue Date FY: 1999 ( Subtotal = $232,018 )
1999	1999	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	000	10	6/22/1999	NON-COMPETING CONTINUATION	$232,018
														Subtotal = $232,018

Issue Date FY: 1998 ( Subtotal = $246,742 )
1998	1998	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Aging Research	000	9	11/19/1998	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$151,055
1998	1998	PICOWER INSTITUTE FOR MEDICAL RESEARCH	350 COMMUNITY DRIVE	MANHASSET	NY	11030	NASSAU	USA	Aging Research	000	8	11/19/1998	NON-COMPETING CONTINUATION	$95,687
														Subtotal = $246,742

Grand Total All Awards = $3,046,285

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AGING AND VASCULAR DISEASE: ROLE OF GLYCATION

Award Number: R01AG009453

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/1992

PERIOD OF PERFORMANCE END DATE: 04/30/2008

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