Date of Award

12-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering and Sciences

First Advisor

Melissa Borgen

Second Advisor

Timothy A. Crombie

Third Advisor

Kenia Pedrosa Nunes

Fourth Advisor

Ralph Turingan

Abstract

The heat shock response (HSR) is a cytoprotective stress response pathway that regulates cellular proteostasis. The HSR is an evolutionarily conserved pathway that is essential for normal cellular functioning. Here, we explore the broad ecological and pathological impacts of the HSR. In an ecological context, we perform gene level analysis of the transcriptomes of two closely related sunfish. We found that the more invasive bluegill sunfish has gene expansions in two HSR gene families, the HSP70 family and the HSP90 family compared to the redear sunfish. These gene expansions were also observed in several other teleost fish species and were found to correlate with invasiveness. This data indicates that genetic analysis of the HSR could be an indicator of invasive potential in fish and other species. In a pathological context, we investigated the plausibility of the HSR as a therapeutic strategy in the treatment of protein misfolding diseases. Alzheimer’s disease is associated with the misfolding of both tau and beta-amyloid proteins. It has previously been shown that HSR activation reduces beta-amyloid toxicity. We found that HSR activation is also protective against tau toxicity. Excitingly, small molecule activation of the HSR via arimoclomol (AC) and geranylgeranylacetone (GGA) was found to have substantial beneficial effects. Taken together, the data presented here contributes to our understanding of the important HSR pathway and expands its wide ranging applications.

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