This Program proposes an overarching hypothesis that rational targeting of ?-secretase, a multi-subunit intramembrane cleaving protease that has several biologically important substrates, may be considered as a therapeutic target for a number of diseases. The three projects in this Program address the use of ?-secretase inhibitors in breast cancer (Project 1), and graft-versus-host disease (Project 2), and propose biochemical strategies to enable us to better understand the mechanism of action of ?-secretase (Project 3). These projects are integrated with a goal of better understanding the mechanism of action of ?-secretase inhibition in normal, as well as, disease settings. The Principal Investigators of this Program have worked together, shared data and published as a group for the past six years. The Program is significantly enhanced by a Chemistry Core that has the proven ability to synthesize a wide variety of ?-secretase inhibitors that allow members of the Program to explore the biological properties of these inhibitors in an environment free from commercial restriction. Such an approach will provide a scientific basis for optimal GSI selection matched to a particular disease.

Public Health Relevance

The development of y-secretase inhibitors targeted for therapy of diseases such as cancer and graft-versus host- disease is likely to significantly impact the treatment of these two important diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA166009-01A1
Application #
8415150
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (O1))
Program Officer
Spalholz, Barbara A
Project Start
2013-09-20
Project End
2017-08-31
Budget Start
2013-09-20
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$980,825
Indirect Cost
$163,430
Name
University of Massachusetts Amherst
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
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