Research Interest: We are interested in harnessing the intrinsic cyto-protective function of heat shock protein chaperones (HSPs) to counter the pathobiology of protein mis-folding diseases including neurodegenerative diseases such as Huntington's, Lou Gehrig's, Alzheimer's , Parkinson's, and prion diseases as well as diabetes and cataract.
HSF1 is an evolutionarily conserved master regulator that mediates the induction of Heat Shock Protein (HSP) chaperones under stress. In higher eukaryotic cells, HSF1 exists as a latent monomer under normal growth conditions. Stress such as an increase in temperature triggers a conformation change in HSF1 to result in the trimerization, nuclear translocation, and activation of HSF1 for an increased production of HSP chaperones. Collectively, this is termed the heat shock response (HSR) and functions principally as a "pro-survival" mechanism under stress. Indeed, there is a large body of evidence that HSP chaperones have a central role in maintaining protein homeostasis (proteostasis) and function as a quality control mechanism to mediate the folding/re-folding and trafficking of cellular proteins, as well as to direct damaged and un-salvageable proteins to degradation machineries in cells.
In previous studies, we showed that HSF1 becomes dysfunctional upon aging and particularly in neuronal cells. This chansge is likely to contribute to neuronal vulnerability in the aged, and hews to the line that age is a primary risk factor for neurodegenerative diseases. Our more recent effort is directed towards the identification and use of small molecules such as riluzole, resveratrol and HSP90 inhibitors to promote and support the activation of HSF1. We found that combinations of these drugs have a synergistic effect in promoting the activation of HSF1, in supporting a robust induction of HSP chaperones, and in mitigating and suppressing the aggregation of mutant polyQ-huntingtin protein in cell model system of Huntington's disease. Our goal is to harness the HSF1/HSP mechanism for protein misfolding diseases.