Characterization of the Role of Caloric Restriction and Sir2.1 in the Heat Shock Response

The heat shock response (HSR) enables an organism to manage protein damaging stress through the activation of the transcription factor HSF1 and the induction of heat shock proteins (hsps). Understanding how the HSR is regulated is important as manipulating this response may be therapeutically beneficial for neurodegenerative disease and cancer. Previously, we have shown that the NAD+-dependent deactylase SIRT1 positively regulates the HSR, thus providing a direct link between the HSR and metabolism. We are further investigating this link using the nematode C. elegans. Caloric restriction (CR) induces the HSR and has been associated with longevity in C. elegans. We show here that heat shock and CR have a synergistic effect in inducing hsp genes. To determine if this effect depends on Sir2.1 (the C. elegans SIRT1 homolog) we will knockdown this gene using RNAi and expect to see a loss of synergy. In addition, we have analyzed the cytoprotective effect that induction of the HSR has on the ability of C. elegans to survive a lethal heat stress. We expect to see that both heat shock and CR promote increased survivability. This study will shed light on the effect of metabolism on the HSR and cytoprotection