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CARDIOMYOPATHY:PRO-OXIDANT ROLE OF ZIDOVUDINE (AZT)

Award Number: R01HL065178
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2000
PERIOD OF PERFORMANCE END DATE: 05/31/2008

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CARDIOMYOPATHY:PRO-OXIDANT ROLE OF ZIDOVUDINE (AZT) - DESCRIPTION (Provided by applicant): Cardiotoxicity seen in HIV patients receiving long-term treatment with zidovudine (AZT) may occur against a background of multiple risk factors: abnormal tissue iron status, nutritional Mg-deficiency (MgD), inflammation and oxidative stress. This proposal will evaluate if chronic AZT treatment synergizes with co-existing MgD to enhance iron imbalance, and resultant oxidative stress in vivo. Recent data from our lab also suggest that AZT-mediated gut injury may promote subsequent endotoxic injury to cardiac and hepatic tissue. This led us to propose the following Specific Aims: (1) Determine if AZT causes systemic oxidative stress, tissue inflammation, and altered tissue iron status in chronically-treated rats and in inflammatory cell models. (2) Assess whether chelation or antibiotic therapy attenuates endotoxemia, indices of tissue and cell oxidative stress, and tissue inflammation in chronic AZT-treated animals. (3) Evaluate if AZT treatment synergizes with MgD to enhance tissue injury in vivo due to increased iron disturbances; and assess the protective efficacy of chelation and antibiotic therapy. (4) Determine if AZT treatment synergizes with MgD to enhance myocardial susceptibility to imposed I/R stress ex vivo; and assess the protective efficacy of in vivo chelation therapy. Sensitive immunocytochemical and molecular biology techniques will be used to localize and quantify cytokines, adhesion molecules, and apoptosis in the myocardium. Oxidative stress will be determined by measuring tissue glutathione and protein-thiol status, lipid peroxidation products, nitric oxide and peroxynitrite marker, as well as free radical production (ESR spin-trapping) and dysfunction in isolated ischemia/reperfused hearts. The main goal is to assess whether AZT, in conjunction with MgD, will further alter iron status, leading to enhanced sensitivity of cardiac, hepatic and intestinal tissue to oxidative stress. The proposed iron chelation and antibiotic intervention strategies may lead to adjunct therapies aimed at lessen AZT-related cardiovascular toxicity.


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 = $326,412 )
2007	2007	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	8	5/23/2007	NON-COMPETING CONTINUATION	$326,412
														Subtotal = $326,412

Issue Date FY: 2006 ( Subtotal = $336,161 )
2006	2006	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	7	5/2/2006	NON-COMPETING CONTINUATION	$336,161
														Subtotal = $336,161

Issue Date FY: 2005 ( Subtotal = $344,250 )
2005	2005	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	6	5/2/2005	NON-COMPETING CONTINUATION	$344,250
														Subtotal = $344,250

Issue Date FY: 2004 ( Subtotal = $344,250 )
2004	2004	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	5	8/13/2004	COMPETING CONTINUATION	$344,250
														Subtotal = $344,250

Issue Date FY: 2003 ( Subtotal = $342,000 )
2003	2003	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	4		NON-COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2002 ( Subtotal = $342,000 )
2002	2002	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	3	3/6/2002	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2001 ( Subtotal = $342,000 )
2001	2001	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	2	2/26/2001	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2000 ( Subtotal = $342,375 )
2000	2000	GEORGE WASHINGTON UNIVERSITY	44983 KNOLL SQUARE	ASHBURN	VA	20147	LOUDOUN	USA	Cardiovascular Diseases Research	000	1	4/24/2000	NEW	$342,375
														Subtotal = $342,375

Grand Total All Awards = $2,719,448

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CARDIOMYOPATHY:PRO-OXIDANT ROLE OF ZIDOVUDINE (AZT)

Award Number: R01HL065178

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2000

PERIOD OF PERFORMANCE END DATE: 05/31/2008

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