Vascular diseases remain major causes of morbidity and mortality in the world. The availability of noninvasive imaging modalities for detection of features such as vessel wall inflammation and remodeling that are involved in, and increase the risk of vascular complications can help reduce this morbidity and mortality. Major existing gaps in the traditional approach to vascular imaging may be addressed by molecular imaging aimed at detecting relevant targets in vivo. To this means, tracers with broad specificity for matrix metalloproteinases (MMPs) have been developed and used to detect vascular remodeling and inflammation in vivo. While promising as first line agents, the effectiveness of these broadly specific agents is limited by diverse and at times opposing effects of different members of the MMP family in the pathogenesis of vascular remodeling and inflammation. Macrophage elastase (MMP-12) plays a key role in the development of atherosclerosis and aneurysm. RXP470, a selective and potent inhibitor of MMP-12, inhibits atherosclerotic plaque development and promotes a stable plaque phenotype. Here, we hypothesize that vessel wall inflammation and remodeling in atherosclerosis and aneurysm can be detected by molecular imaging of activated MMP-12 in vivo.
Our specific aims are to develop and validate novel MMP-12-targeted tracers for molecular imaging and to validate the active form of MMP-12 as a marker of macrophage activation and target for imaging of vascular inflammation and remodeling in aneurysm and atherosclerosis. Based on the structure of RXP470 we have developed and preliminarily tested novel fluorescent and radiolabeled probes for molecular imaging. Here, this portfolio of tracers will be expanded and optimized for molecular imaging. The effectiveness of activated MMP-12 as a marker of inflammatory and vascular cell activation and differentiation will be addressed. Finally, complementary murine models of aneurysm and atherosclerosis will be used to validate MMP-12-targeted imaging for detection of vessel wall inflammation and remodeling by fluorescent imaging ex vivo and SPECT imaging in vivo. If validated, MMP-12 targeted imaging may identify patients at risk for acute coronary syndromes and aneurysm rupture and help track the effect of novel therapeutic interventions in vascular diseases.

Public Health Relevance

We plan to develop novel tracers for non-invasive imaging of inflammation in aneurysm and atherosclerosis to identify patients who are at high risk for heart attack and aneurysm rupture. This should lead to a reduction in vascular deaths.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL112992-02
Application #
8608590
Study Section
Special Emphasis Panel (ZRG1-SBIB-Q (06))
Program Officer
Danthi, Narasimhan
Project Start
2013-02-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$474,202
Indirect Cost
$154,212
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Bordenave, Thomas; Helle, Marion; Beau, Fabrice et al. (2016) Synthesis and in Vitro and in Vivo Evaluation of MMP-12 Selective Optical Probes. Bioconjug Chem 27:2407-2417
Li, Xuan; Jung, Jae-Joon; Nie, Lei et al. (2016) The neuropilin-like protein ESDN regulates insulin signaling and sensitivity. Am J Physiol Heart Circ Physiol 310:H1184-93
Golestani, Reza; Razavian, Mahmoud; Ye, Yunpeng et al. (2016) Matrix metalloproteinase-targeted imaging of lung inflammation and remodeling. J Nucl Med :
Golestani, Reza; Jung, Jae-Joon; Sadeghi, Mehran M (2016) Molecular Imaging of Angiogenesis and Vascular Remodeling in Cardiovascular Pathology. J Clin Med 5:
Toczek, Jakub; Meadows, Judith L; Sadeghi, Mehran M (2016) Novel Molecular Imaging Approaches to Abdominal Aortic Aneurysm Risk Stratification. Circ Cardiovasc Imaging 9:e003023
Jung, Jae-Joon; Razavian, Mahmoud; Kim, Hye-Yeong et al. (2016) Matrix metalloproteinase inhibitor, doxycycline and progression of calcific aortic valve disease in hyperlipidemic mice. Sci Rep 6:32659
Sadeghi, Mehran M (2016) Molecular cardiovascular imaging is ready for prime time: almost there. J Nucl Cardiol 23:67-70
Toczek, Jakub; Sadeghi, Mehran M (2016) A New Tracer for Imaging Atherosclerosis. Circ Cardiovasc Imaging 9:
Toczek, Jakub; Sadeghi, Mehran M (2016) Molecular imaging concepts. J Nucl Cardiol 23:271-3
Jung, Jae-Joon; Razavian, Mahmoud; Challa, Azariyas A et al. (2015) Multimodality and molecular imaging of matrix metalloproteinase activation in calcific aortic valve disease. J Nucl Med 56:933-8

Showing the most recent 10 out of 17 publications