- Email: [email protected]
Project title Re-Endothelialization of arteries after angioplasty
diabetes mellitus, enzyme substrate, heart contraction, heart failure, insulin, isocitrate dehydrogenase, mitochondria, oxidation, oxoglutarate dehydrogenase, oxygen consumption, pyruvate dehydrogenase, succinate dehydrogenase histology, isolation perfusion, laboratory rat, nuclear magnetic resonance spectroscopy
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 1998 Radiology 01-Jan-95 31-Dec-98 National Heart, Lung, And Blood Institute MET
)ROJECT TITLE RE-ENDOTHELIALIZATION OF ARTERIES AFTER ANGIOPLASTY Grant Number: PI Name:
5R01HL55508-03 Consigny, Paul M.
Abstract: DESCRIPTION (adapted from the applicant's abstract): Balloon angioplasty has become a popular technique for the treatment of atherosclerotic lesions. However, angioplasty has one very significant problem - in up to half of the successfully treated clinical cases, the lesions reappears, usually within 6 to 12 months. This recurrence or restenosis is the result of intimal thickening, secondary to cell proliferation and extracellular matrix deposition, and a failure of the artei-y to remodel. The overall objective of the proposed research is to determine if restenosis after balloon angioplasty of the rabbit iliac arteries can be prevented by coating the luminal surface of the dilated artery with endothelial cells previously obtained from the rabbit's adipose tissue. The first aim of this study is to determine the method which provides maximal endothelial cell retention on the luminal surface of the balloon dilated artery. In vitro experiments will be performed to determine if the adhesion of the endothelial cells to matrix can be augmented by stimulating integrin and/or nonintegrin mediated adhesion. Endothelial cell adhesion will be measured under static conditions (retention on matrix-coated culture cells) and dynamic conditions (retention on matrixcoated microscope slides placed in a parallel plate flow apparatus and exposed to shear). Integrin-mediated adhesion will be augmented by treating the endothelial cells with protein kinase C activators, growth factors, or protein kinase A inhibitors. Non-integrin mediated adhesion will be promoted by simulating transglutaminase activity. Additional short term in vivo experiments, which measure the adhesion and retention
468
of fluorescently-labeled endothelial cells to balloon dilated rabbit external iliac arteries using epifluorescence microscopy, will be performed to determine if simulation of integrin or non-integrin mediated endothelial cell adhesion improves endothelial cell retention, and if modifications to the cell delivery technique can improve cell retention. Modifications that will be tested include rotation of the rabbit during endothelial cell placement. The second aim of this study is to determine if the placement of endothelial cells on the luminal surface of balloon dilated arteries, using the method which provides maximal endothelial cell coverage, will reduce intireal thickening and promote arterial enlargement. Long-term in vivo experiments will be performed in which the method that provides the best endothelial cell retention will be used to place endothelial cells on one balloon dilated rabbit iliac artery; the contralateral balloon-dilated iliac artery will serve as a control. Four weeks thereafter, the effectiveness of the re-endothelialization procedure will be determined by comparing arteriographic diameters, intimal areas, and circumferences of internal and elastic laminae for the treatment of control arteries. Thesaurus Terms: angiogenesis, artery stenosis, intraluminal angioplasty, vascular endothelium arteriosclerosis, autologous transplantation, cell adhesion, cell growth regulation, cell transplantation, histopathology, integrin, restenosis, surface coating laboratory rabbit
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Thomas Jefferson University 1020 Walnut St Philadelphia, PA 19107 1998 Radiology 01-Aug-96 30-Jun-00 National Heart, Lung, And Blood Institute CVA
'ROJECT TITLE MECHANISTIC STUDIES OF META IODOBENZYLGUANIDINE IN HEART Grant Number: PI Name
5R29HL54882-03 Degrado, Timothy R.
Abstract: DESCRIPTION: The kinetics of 1-131 labeled meta-iodobenzylguanidine (MIBG) in the heart will be studied using an isolated perfused rat heart model. Uptake, retention and release of 1-131-MIBG will be studied under various conditions and correlated with variables such as catecholamine transport and metabolism, ischemia, and variations in cardiac metabolic substrate. Neuronal and extraneuronal uptake will be distinguished using agents that block specific
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 1998 Radiology 01-Jan-95 31-Dec-98 National Heart, Lung, And Blood Institute MET
)ROJECT TITLE RE-ENDOTHELIALIZATION OF ARTERIES AFTER ANGIOPLASTY Grant Number: PI Name:
5R01HL55508-03 Consigny, Paul M.
Abstract: DESCRIPTION (adapted from the applicant's abstract): Balloon angioplasty has become a popular technique for the treatment of atherosclerotic lesions. However, angioplasty has one very significant problem - in up to half of the successfully treated clinical cases, the lesions reappears, usually within 6 to 12 months. This recurrence or restenosis is the result of intimal thickening, secondary to cell proliferation and extracellular matrix deposition, and a failure of the artei-y to remodel. The overall objective of the proposed research is to determine if restenosis after balloon angioplasty of the rabbit iliac arteries can be prevented by coating the luminal surface of the dilated artery with endothelial cells previously obtained from the rabbit's adipose tissue. The first aim of this study is to determine the method which provides maximal endothelial cell retention on the luminal surface of the balloon dilated artery. In vitro experiments will be performed to determine if the adhesion of the endothelial cells to matrix can be augmented by stimulating integrin and/or nonintegrin mediated adhesion. Endothelial cell adhesion will be measured under static conditions (retention on matrix-coated culture cells) and dynamic conditions (retention on matrixcoated microscope slides placed in a parallel plate flow apparatus and exposed to shear). Integrin-mediated adhesion will be augmented by treating the endothelial cells with protein kinase C activators, growth factors, or protein kinase A inhibitors. Non-integrin mediated adhesion will be promoted by simulating transglutaminase activity. Additional short term in vivo experiments, which measure the adhesion and retention
468
of fluorescently-labeled endothelial cells to balloon dilated rabbit external iliac arteries using epifluorescence microscopy, will be performed to determine if simulation of integrin or non-integrin mediated endothelial cell adhesion improves endothelial cell retention, and if modifications to the cell delivery technique can improve cell retention. Modifications that will be tested include rotation of the rabbit during endothelial cell placement. The second aim of this study is to determine if the placement of endothelial cells on the luminal surface of balloon dilated arteries, using the method which provides maximal endothelial cell coverage, will reduce intireal thickening and promote arterial enlargement. Long-term in vivo experiments will be performed in which the method that provides the best endothelial cell retention will be used to place endothelial cells on one balloon dilated rabbit iliac artery; the contralateral balloon-dilated iliac artery will serve as a control. Four weeks thereafter, the effectiveness of the re-endothelialization procedure will be determined by comparing arteriographic diameters, intimal areas, and circumferences of internal and elastic laminae for the treatment of control arteries. Thesaurus Terms: angiogenesis, artery stenosis, intraluminal angioplasty, vascular endothelium arteriosclerosis, autologous transplantation, cell adhesion, cell growth regulation, cell transplantation, histopathology, integrin, restenosis, surface coating laboratory rabbit
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Thomas Jefferson University 1020 Walnut St Philadelphia, PA 19107 1998 Radiology 01-Aug-96 30-Jun-00 National Heart, Lung, And Blood Institute CVA
'ROJECT TITLE MECHANISTIC STUDIES OF META IODOBENZYLGUANIDINE IN HEART Grant Number: PI Name
5R29HL54882-03 Degrado, Timothy R.
Abstract: DESCRIPTION: The kinetics of 1-131 labeled meta-iodobenzylguanidine (MIBG) in the heart will be studied using an isolated perfused rat heart model. Uptake, retention and release of 1-131-MIBG will be studied under various conditions and correlated with variables such as catecholamine transport and metabolism, ischemia, and variations in cardiac metabolic substrate. Neuronal and extraneuronal uptake will be distinguished using agents that block specific