Molecular chaperones are key players in the maintenance of a healthy proteome and in homeostasis of the cell. Dysregulation in the function of molecular chaperones leads to many metabolic, oncological, neurodegenerative, and cardiovascular diseases. The Hsp90 chaperoning machine, in particular, involves a number of chaperones and co-chaperones that, through a complex network of interactions, ensure the folding and the functionality of many key regulatory proteins. Current information suggests that targeting this machine may have a significant and combinatorial impact on dysfunctional circuitries that underlie human diseases such as cancer and neurodegenerative diseases. Novel small-molecule compounds that target the Hsp90 machine in a selective manner are needed. They will provide tools and molecular probes to further dissect the biology of this machine to better understand its role in disease etiology and progression, and to facilitate the subsequent development of therapeutics against relevant targets. This application aims to develop a high- throughput assay based on progesterone and glucocorticoid receptors, which are physiological clients of Hsp90, and the core components of the Hsp90 chaperoning machine (Hsp90, Hsp70, Hsp40, Hop, and p23). This assay would significantly enhance the discovery of chemical probes that would affect the functional core of the Hsp90 machine. It would also provide the long sought-after screening tool for specific inhibitors of Hsp90 alpha and beta isoforms and facilitate the identification of molecular targets of active compounds.

Public Health Relevance

This project aims to develop a new high-throughput assay to discover novel inhibitors of molecular chaperones, which could eventually be developed as drugs against cancer and other human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM102443-01
Application #
8344548
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fabian, Miles
Project Start
2012-07-15
Project End
2015-04-30
Budget Start
2012-07-15
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$240,247
Indirect Cost
$69,697
Name
Georgia Regents University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912