Aneurysmal disease of the aorta is a common cause of death in the United States. Thoracic aortic aneurysm (TAA) patients are particularly challenging because of the complexity of surgical repair and high incidence of postoperative morbidity. Aortic aneurysms represent a vascular remodeling process characterized by loss of the aortic medial layer caused, at least in part, by degradation of the extracellular matrix (ECM). The overall goal of this project is to define the extracellular mechanisms contributing to the progression of TAA. The matrix metalloproteinases (MMPs) degrade the ECM both in health and disease. MMPs and their tissue inhibitors (TIMPs) are produced by many cell types including those found in the aorta. Past clinical studies have suggested an imbalance occurs between MMPs and TIMPs in resected aortic aneurysms. The central hypotheses of this project are that alterations in MMP/TIMP stoichiometry is an early event in TAA progression; that targeted modulation of MMP/TIMP stoichiometry will directly modify TAA progression; and that a fundamental cellular mechanism for TAA progression is regional alterations in fibroblast MMP/TIMP expression. Using a murine model of TAA developed in this laboratory, this project will accomplish the following aims: (1) Establish the temporal-spatial relationship of TAA progression to local MMP/TIMP levels; (2) Modify the natural history of TAA through targeted MMP-9 gene deletion (MMP loss of function) or TIMP- 1 gene deletion (MMP gain of function); (3) Establish that MMP-9 gene induction is an early event in TAA progression and that a fundamental cell type responsible for abnormal MMP/TIMP expression is the fibroblast. The outcomes from this project will establish mechanistic insight into the formation and progression of thoracic aneurysms and provide the basis for rational designs for therapeutic modulation in patients with this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075488-05
Application #
7326817
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Goldman, Stephen
Project Start
2003-12-01
Project End
2008-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
5
Fiscal Year
2008
Total Cost
$311,478
Indirect Cost
Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Ruddy, Jean Marie; Ikonomidis, John S; Jones, Jeffrey A (2016) Multidimensional Contribution of Matrix Metalloproteinases to Atherosclerotic Plaque Vulnerability: Multiple Mechanisms of Inhibition to Promote Stability. J Vasc Res 53:1-16
Jones, Jeffrey A; Zavadzkas, Juozas A; Chang, Eileen I et al. (2010) Cellular phenotype transformation occurs during thoracic aortic aneurysm development. J Thorac Cardiovasc Surg 140:653-9
Ruddy, Jean Marie; Jones, Jeffrey A; Stroud, Robert E et al. (2010) Differential effect of wall tension on matrix metalloproteinase promoter activation in the thoracic aorta. J Surg Res 160:333-9
Jones, Jeffrey A; Ikonomidis, John S (2010) The pathogenesis of aortopathy in Marfan syndrome and related diseases. Curr Cardiol Rep 12:99-107
Jones, Jeffrey A; Ruddy, Jean Marie; Bouges, Shenikqua et al. (2010) Alterations in membrane type-1 matrix metalloproteinase abundance after the induction of thoracic aortic aneurysm in a murine model. Am J Physiol Heart Circ Physiol 299:H114-24
Ruddy, Jean Marie; Jones, Jeffrey A; Stroud, Robert E et al. (2009) Differential effects of mechanical and biological stimuli on matrix metalloproteinase promoter activation in the thoracic aorta. Circulation 120:S262-8
Jones, Jeffrey A; Spinale, Francis G; Ikonomidis, John S (2009) Transforming growth factor-beta signaling in thoracic aortic aneurysm development: a paradox in pathogenesis. J Vasc Res 46:119-37
Jones, Jeffrey A; Beck, Christy; Barbour, John R et al. (2009) Alterations in aortic cellular constituents during thoracic aortic aneurysm development: myofibroblast-mediated vascular remodeling. Am J Pathol 175:1746-56
Ruddy, Jean Marie; Jones, Jeffrey A; Spinale, Francis G et al. (2008) Regional heterogeneity within the aorta: relevance to aneurysm disease. J Thorac Cardiovasc Surg 136:1123-30
Ford, Rachael L; Mains, Ira M; Hilton, Ebony J et al. (2008) Endothelin-A receptor inhibition after cardiopulmonary bypass: cytokines and receptor activation. Ann Thorac Surg 86:1576-83

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