Whitehead Fellow


David Pincus

Fellow, Whitehead Institute



We are trying to reveal the underlying mechanisms cells employ to maintain homeostasis in inherently fluctuating environments. Any change in the surroundings – be it a change in temperature, pH, the amount of salt, the availability of nutrients, etc. – is an excursion away from equilibrium and a challenge to the cell. By understanding at the molecular level how cells sense and respond to these inevitable environmental fluctuations, we strive to ascertain the limits that healthy cells can cope with, the pathways responsible for coping, and how these pathways can break down or be hijacked in various disease states such as diabetes and cancer.

The goal of our efforts is to define common control strategies that cells employ to regulate their activities when faced with environmental perturbations. To approach the problem experimentally, we use the budding yeast Saccharomyces cerevisiae as a model organism to interrogate signaling in stress response pathways, using the regulation of the highly conserved Heat Shock Factor (HSF) as an initial test bed. We aim to answer the following questions: 1) What is the relationship between expression level of HSF and its activity? 2) How does phosphorylation of HSF contribute to HSF activity? 3) How do interactions with chaperone proteins regulate HSF? 4) How do expression level, phosphorylation and chaperone protein interactions coordinate an appropriate response in real time to different perturbations?

By answering these questions – and in the process developing widely applicable approaches to paint quantitative and mechanistic portraits of stress adaptation – we strive to ascertain both specific instantiations as well as general principles that control cellular stress responses to maintain homeostasis and maximize fitness.

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