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RESTENOSIS AND ENDOTHELIAL PROLIFERATION

Award Number: R01HL063414
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/1999
PERIOD OF PERFORMANCE END DATE: 06/30/2008

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RESTENOSIS AND ENDOTHELIAL PROLIFERATION - DESCRIPTION (provided by applicant): While percutaneous delivery of endovascular stents has been shown to reduce the frequency, restenosis still complicates 22-28% of stented coronary arteries despite advances in stent deployment techniques. Neointimal thickening has been inferred to result most often from vascular smooth muscle cell (SMC) proliferation. Strategies targeting this phenomenon have reduced the incidence of restenosis, however there also appears to be evidence for impaired endothelial recovery associated with brachytherapy and perhaps antiproliferative drug eluting stents. Previous studies carded out in a variety of animal species have repeatedly shown that extensive endothelial denudation of the artery wall promotes neointimal thickening. We have therefore considered the possibility that those stents which develop refractory intimal thickening, as well as a portion of restenosis lesions which originate in non-stented arteries or bypass grafts post-PTCA, may result in part from belated endothelial recovery. We have now developed substantial evidence that tumor necrosis factor alpha (TNF), which is expressed at sites of balloon injury, can impair endothelial recovery by inhibiting the proliferation of endothelial cells adjacent to the site of injury. Our studies also show that endothelial recovery can be improved by blocking TNF's effects. Recently we have discovered that TNF activates a novel transcription factor function of Ezrin, formerly thought to be a cytoskeletal protein, which results in the inhibition of certain cell cycle promoters. We have found that TNF specifically inhibits the activity of another transcription factor, E2F1, which normally promotes proliferation. Finally, we have evidence that circulating, bone marrow derived endothelial progenitor cells contribute to the recovery of the endothelium at sites of injury and that TNF also inhibits the proliferation of these cells. In Specific Aim 1 we will investigate the mechanisms by which Ezrin inhibits EC proliferation and determine if inhibition of Ezrin activity can result in improved endothelial recovery in vivo. In Specific Aim 2 we will investigate the effect of Ezrin on bone marrow derived endothelial progenitor cells and determine the impact on re-endothelializaiton. In Specific Aim 3 we will investigate mechanisms responsible for repression of E2F1 activity and evaluate the effect of inhibition of this effect on ReEndo. Together these studies will result in a better understanding of the mechanisms, which govern EC recovery at sites of balloon injury and may lead to novel therapeutic strategies targeting endothelial recovery.


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 = $354,556 )
2007	2007	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60201	COOK	USA	Cardiovascular Diseases Research	000	8	6/29/2007	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$354,556
														Subtotal = $354,556

Issue Date FY: 2006 ( Subtotal = $384,794 )
2006	2006	CARITAS ST ELIZABETH`S MEDICAL CENTER OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Cardiovascular Diseases Research	000	7	3/27/2006	NON-COMPETING CONTINUATION	$384,794
														Subtotal = $384,794

Issue Date FY: 2005 ( Subtotal = $382,581 )
2005	2005	ST ELIZABETH'S HOSPITAL OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Cardiovascular Diseases Research	000	6	2/28/2005	NON-COMPETING CONTINUATION	$382,581
														Subtotal = $382,581

Issue Date FY: 2004 ( Subtotal = $371,437 )
2004	2004	ST ELIZABETH'S HOSPITAL OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Cardiovascular Diseases Research	000	5	4/22/2004	COMPETING CONTINUATION	$371,437
														Subtotal = $371,437

Issue Date FY: 2002 ( Subtotal = $359,385 )
2002	2002	ST ELIZABETH'S HOSPITAL OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Cardiovascular Diseases Research	000	4	7/22/2002	NON-COMPETING CONTINUATION	$359,385
														Subtotal = $359,385

Issue Date FY: 2001 ( Subtotal = $352,209 )
2001	2001	ST ELIZABETH'S HOSPITAL OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	7/19/2001	NON-COMPETING CONTINUATION	$352,209
														Subtotal = $352,209

Issue Date FY: 2000 ( Subtotal = $341,386 )
2000	2000	CARITAS ST ELIZABETH`S MEDICAL CENTER OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	7/21/2000	NON-COMPETING CONTINUATION	$341,386
														Subtotal = $341,386

Issue Date FY: 1999 ( Subtotal = $340,576 )
1999	1999	CARITAS ST ELIZABETH`S MEDICAL CENTER OF BOSTON	736 CAMBRIDGE ST, BOX OLH-6BD	BOSTON	MA	02135	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	8/13/1999	NEW	$340,576
														Subtotal = $340,576

Grand Total All Awards = $2,886,924

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RESTENOSIS AND ENDOTHELIAL PROLIFERATION

Award Number: R01HL063414

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/1999

PERIOD OF PERFORMANCE END DATE: 06/30/2008

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