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GROWTH FACTOR MEDIATION OF HEALING OF VASCULAR GRAFTS

Award Number: R01HL041272
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: HEALTH SERVICES
PERIOD OF PERFORMANCE START DATE: 07/01/1988
PERIOD OF PERFORMANCE END DATE: 05/31/2007

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GROWTH FACTOR MEDIATION OF HEALING OF VASCULAR GRAFTS - DESCRIPTION (provided by applicant): The two common failure modes of therapeutic vascular interventions are early thrombosis and late myointimal hyperptasia, both likely to be reduced by a functioning endothelial cell (EC) monolayer. We have developed a novel method of controlled local delivery of bioactive growth factors to vascular tissues and grafts yielding potent in vivo angiogenesis and surface endothelialization. Our recent studies generated and characterized mutant FGF-1 species with likely more efficacious biological properties. The overall hypotheses are that 1) the R136K mutation of FGF-1 will yield resistance to proteolytic degradation while maintaining or augmenting bioactivity, 2) that additional logically derived structural alterations will increase EC specificity and potency of the mitogenic and angiogenic signals and that 3) local delivery of the derived construct via fibrin hydrogels or as a chimera with a collagen binding domain wilt promote in vivo endothetiaUzation without a concomitant myointimal hyperplasia. These:hypotheses are supported by strong in vitro data that FGF.1 specificity and potency can be altered by mutagenesis, that the RI36K mutation at the proteolytic site promotes molecular and biological :stability and that fusing the peptides to HB-GAM promotes EC specificity. The proposal has 3 Specific Aims. Specific Aim #1A): Characterization of existing and next generation R136K based mutant/chimeric proteins based on existing assays of molecular stability and of relevant biological functions using our established method of local delivery, and 1B): elucidation of mechanisms of action responsible for increased R136K mitogenic activity and incorporation of that knowledge into the design of novel mutant chimeras likely to exhibit desirable in vivo activities. Specific Aim #2: Determine using in vitro assays whether a chimeric protein: consisting of the R136K form of FGF-1 and a collagen binding domain derived :from C. histolyticum cotlagenase would further promote endothelialization using vascular intramural delivery. Specific Aim #3: Evaluate in vivo cell-specific responses to the in vitro-optimized mutant/chimera using application-specific delivery by fibdn glue or by matrix collagen targeting in well characterized animal models of bypass grafting and of endarterectomy. We strongly believe that results will be directly clinically applicable in vascular interventions and should provide an enabling technology for a broad range of tissue engineering strategies.


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: 2006 ( Subtotal = $293,453 )
2006	2006	LOYOLA UNIVERSITY MEDICAL CENTER	820 N MICHIGAN AVENUE	CHICAGO	IL	60611	COOK	USA	Cardiovascular Diseases Research	000	18	7/3/2006	NON-COMPETING CONTINUATION	$293,453
														Subtotal = $293,453

Issue Date FY: 2005 ( Subtotal = $289,638 )
2005	2005	LOYOLA UNIVERSITY MEDICAL CENTER							Cardiovascular Diseases Research	000	17	5/30/2005	NON-COMPETING CONTINUATION	$289,638
														Subtotal = $289,638

Issue Date FY: 2004 ( Subtotal = $280,036 )
2004	2004	LOYOLA UNIVERSITY MEDICAL CENTER							Cardiovascular Diseases Research	000	16	5/26/2004	NON-COMPETING CONTINUATION	$280,036
														Subtotal = $280,036

Issue Date FY: 2003 ( Subtotal = $349,824 )
2003	2003	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cardiovascular Diseases Research	000	15	9/29/2003	COMPETING CONTINUATION	$349,824
														Subtotal = $349,824

Issue Date FY: 2002 ( Subtotal = $286,626 )
2002	2002	LOYOLA UNIVERSITY MEDICAL CENTER	2160 SOUTH FIRST AVENUE	MAYWOOD	IL	60153	COOK	USA	Cardiovascular Diseases Research	000	14	11/23/2001	NON-COMPETING CONTINUATION	$286,626
														Subtotal = $286,626

Issue Date FY: 2001 ( Subtotal = $275,529 )
2001	2001	LOYOLA UNIVERSITY MEDICAL CENTER	2160 SOUTH FIRST AVENUE	MAYWOOD	IL	60153	COOK	USA	Cardiovascular Diseases Research	000	13	1/9/2001	NON-COMPETING CONTINUATION	$275,529
														Subtotal = $275,529

Issue Date FY: 2000 ( Subtotal = $264,687 )
2000	2000	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cardiovascular Diseases Research	000	12	12/3/1999	NON-COMPETING CONTINUATION	$264,687
														Subtotal = $264,687

Issue Date FY: 1999 ( Subtotal = $248,336 )
1999	1999	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cardiovascular Diseases Research	000	11	12/4/1998	NON-COMPETING CONTINUATION	$248,336
														Subtotal = $248,336

Issue Date FY: 1998 ( Subtotal = $265,829 )
1998	1998	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cardiovascular Diseases Research	000	10	12/15/1997	COMPETING CONTINUATION	$265,829
														Subtotal = $265,829

Grand Total All Awards = $2,553,958

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GROWTH FACTOR MEDIATION OF HEALING OF VASCULAR GRAFTS

Award Number: R01HL041272

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: HEALTH SERVICES

PERIOD OF PERFORMANCE START DATE: 07/01/1988

PERIOD OF PERFORMANCE END DATE: 05/31/2007

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