Protease activities are known to be critical in the pathogenesis of a wide variety of diseases including cancer, cardiovascular disease, and inflammatory and infectious diseases. Although large-scale efforts are providing valuable information regarding the expression of many diverse proteases in normal and disease tissues, these methods do not report the functional activity of proteases. Protease beacons are emerging as a powerful tool to non-invasively measure protease activity in vivo, and will benefit from approaches that enable more selective cleavage by individual targeted proteases and probe retention at the site of activation. This project aims to validate a generic molecular probe design to detect, localize, and quantify protease activities in vivo in normal and pathologic tissues and whole organisms. Specifically, a new class of protease activity probes will be created that exhibit the desired characteristics of high tissue uptake, selective activation by individual target proteases, and accumulation at sites of activation. The utility of these probes for the localization and quantification of protease activities in vivo will be demonstrated in normal mice and the ApoE(-/-) mouse model of atherosclerosis. Completion of this project will yield probes that accurately and reliably report the activity of proteases involved in normal and pathologic processes, with high potential for translational to humans. More generally, successful completion of the aims of this proposal will open the door to the measurement and localization of a wide range of protease activities in living organisms with high spatial and temporal precision.

Public Health Relevance

This project aims to enable the detection, localization and quantification of a large class of enzymes that play key roles in disease processes, to enable completely new therapeutic approaches and diagnostic tools. We will develop and validate molecular probes that enable measurement of two protease activities that play crucial roles in the progression of cardiovascular disease. !

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM097114-03
Application #
8607966
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Gerratana, Barbara
Project Start
2012-02-15
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
$320,661
Indirect Cost
$71,407
Name
University of California Santa Barbara
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
094878394
City
Santa Barbara
State
CA
Country
United States
Zip Code
93106
Shropshire, Tyler D; Reifert, Jack; Rajagopalan, Sridharan et al. (2014) Amyloid * peptide cleavage by kallikrein 7 attenuates fibril growth and rescues neurons from A*-mediated toxicity in vitro. Biol Chem 395:109-18