While many genome sequencing projects are now complete and it is possible to create complete lists of all protease genes in an entire 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. This proposal outlines plans to develop small molecule activity based probes (ABPs) for functional microscopic imaging of two major classes of cystiene proteases, the cathepsins and caspases. Specifically we plan to 1) develop both general and selective cysteine protease probes that will modify protease targets in complex proteomes 2) develop fluorescently labeled probes that become activated upon modification of a target enzyme and 3) validate the probes using mouse models for ischemia-induced cell death and VEGF-mediated angiogenesis. We plan to use both invasive microscopic methods for high resolution imaging as well as non-invasive methods for direct imaging of protease activities in live animals. Thus, chemical probes have broad applications for basic mechanistic studies as well as for diagnostic imaging in a number of human diseases in which cysteine proteases play a functional role. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB005011-04
Application #
7467390
Study Section
Microscopic Imaging Study Section (MI)
Program Officer
Zhang, Yantian
Project Start
2005-09-30
Project End
2010-02-28
Budget Start
2008-08-01
Budget End
2010-02-28
Support Year
4
Fiscal Year
2008
Total Cost
$331,496
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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