Chaperone Machinery Modulators in Cancer, Cardiovascular Disease and Neurodegeneration
We study protein quality control across translational models of cancer, cardiovascular disease and neurodegeneration with the goal of defining mechanisms of protein homeostasis and identifying therapeutic targets.
Our unified approach is based on the realization that a single cellular machinery, the Hsp90/Hsp70 based chaperone machinery, controls the activity, turnover and trafficking of hundreds of client proteins, and as such plays a critical role in the pathogenesis of these varied disorders.
In contrast to the classic model of individual chaperones interacting with unfolded proteins to facilitate their refolding, we will test a model in which the chaperone machinery functions in protein triage by interacting with client proteins in their near-native conformations to open and stabilize protein folding/ligand binding clefts.
Although chaperone machinery function has been studied intensively, a major limitation in the field is that the mechanism by which it triages unfolded or damaged proteins for degradation is poorly understood.
Our goal is to define this mechanism in order to develop strategies to achieve therapeutic benefits in disease.
Investigators Involved with this Hub:
- Mark Cohen, M.D. - Laboratory Website
- Sharlene Day, M.D. - Laboratory Website
- Jason Gestwicki, Ph.D. - Laboratory Website
- Theodore Lawrence, M.D., Ph.D. - Laboratory Website
- Andrew Lieberman, M.D., Ph.D. - Laboratory Website
- Mukesh Nyati, Ph.D. - Laboratory Website
- Yoichi Osawa, Ph.D. - Laboratory Website
- William Pratt, M.D.
- Daniel Southworth, Ph.D. - Laboratory Website