While we now have relatively complete lists of all proteases expressed in any given organism, our understanding of the functional roles of these enzymes, for the most part, remains largely unclear. The development of new technologies that will allow the imaging of protease activity is a critical step to begin to map out complex proteolytic cascades as well as to validate proteases as biomarkers for human disease. In the first phase of funding for this project we developed fluorescently labeled small molecule activity based probes (ABPs) that target two major classes of cystiene proteases, the cathepsins and caspases. We then demonstrated that fluorescent ABPs could be used for functional, non-invasive imaging studies of these proteases in various mouse models of human cancer. In the next phase of the project we will apply the probes from the initial funding period to mouse models of inflammation and atherosclerosis. We will also engineer several new classes of imaging probes that target proteases that play roles in the regulation of inflammation. These targets include cathepsins S and K, caspases-1, -4 and -5 and the immunoproteasome. We believe that these reagents will expand the use of the ABP technology platform to a large number of important human diseases that involve the process of inflammation.

Public Health Relevance

This project outlines plans to develop fluorescently labeled imaging agents that target proteases involved in the process of inflammation. Specifically these reagents will be used to detect inflammation in atherosclerotic plaques and may ultimately lead to the generation of contrast agents for early diagnosis and disease monitoring using non-invasive imaging methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
2R01EB005011-05A1
Application #
7888534
Study Section
Microscopic Imaging Study Section (MI)
Program Officer
Zhang, Yantian
Project Start
2005-04-01
Project End
2013-12-31
Budget Start
2010-03-01
Budget End
2010-12-31
Support Year
5
Fiscal Year
2010
Total Cost
$364,074
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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