Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)


Biomedical and Chemical Engineering and Sciences

First Advisor

Eric Guisbert

Second Advisor

David Carroll

Third Advisor

Julia Grimwade

Fourth Advisor

Munevver Subasi


Every organism studied to-date utilizes the heat shock response (HSR) to maintain protein-folding homeostasis (proteostasis) during temperature or other protein-folding stress. The HSR has been well characterized using acute heat stress (HS) in single-celled models, but less is known about how distinct cell types and tissues respond to HS. Furthermore, how metazoans respond to prolonged HS at the molecular level remains relatively unexplored. The model organism C. elegans, with its genetic tractability and distinct tissues and behaviors, has been used extensively in the field to characterize the acute HSR, but with considerable variability across labs regarding HS temperature and duration. Our objectives were to standardize HSR methodology and to examine spatiotemporal regulation of the HSR in this nematode by characterizing the effects of HS in different tissues and using extended timescales. These goals were met by combining genetic knockdowns, fluorescent protein reporters, qPCR, transcriptomic analyses, and behavioral assays. First, we demonstrated that the commonly used thermotolerance assay does not rely on the master regulator of the HSR, HSF-1, and instead proposed use of an alternate thermorecovery assay, which does rely on HSF-1, as standard practice for HSR studies. Next, we uncovered tissue-specific responses to proteostasis disruptions that are driven by the balance between ubiquitously expressed HSR components and their tissue-specific substrates. Then, we identified a new cellular pathway affected by chronic HS—endocytosis—which was disrupted in oocytes, coelomocytes, and neurons at different points along a time course of chronic HS. Overexpression of molecular chaperones rescued endocytic defects and partially restored the associated phenotypes, suggesting chaperone titration during chronic HS as the driving mechanism. This mechanism is shared by neurodegenerative disease cell culture models but has not been shown in an intact, multicellular organism or with HS. Finally, we discovered that chronic HS induces activation of the hsf-1 promoter. This is particularly exciting because it has long been believed that HS does not affect hsf-1 transcription, since HSF-1 levels remain stable during a standard acute HS. Together, we have uncovered novel regulation of the HSR across space and time in C. elegans.