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)
Type
Research Program Projects (P01)
Project #
5P01CA166009-02
Application #
8738618
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Spalholz, Barbara A
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Massachusetts Amherst
Department
Veterinary Sciences
Type
Earth Sciences/Resources
DUNS #
City
Amherst
State
MA
Country
United States
Zip Code
01003