Publication Date:
2022-05-25
Description:
Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy
at the
Massachusetts Institute of Technology
and the
Woods Hole Oceanographic Institution
February 2018
Description:
Signaling pathways that respond to stress and sense nutrient availability are highly conserved throughout
eukaryotes. In mammalian cells, these pathways have evolved to regulate immune responses,
representing important therapeutic targets. Interestingly, components of these pathways can be found in
plants, yeast and nematodes, where they also participate in response to abiotic and biotic stress. The
Amino Acid Response (AAR) pathway, an ancient response to the cellular accumulation of uncharged
tRNA, is part of the larger Integrated Stress Response (ISR) in mammals. The ISR consists of multiple
branches, each one triggered by distinct stresses that produce phospho-eIF2α signal generation. Each ISR
initiating stress results in a unique cellular response due to activation of both the ISR and additional
parallel pathway(s) by the initiating stress, but, to date, no such alternate pathway has been identified for
the AAR pathway. Despite its integral role in stress adaptation, the ISR has not been studied in early
diverging animals. I have identified a highly conserved phosphorylation site in the protein eIF2α, the
signature ISR effector, which allowed me to use a mammalian antibody to identify and characterize the
ISR in the basal metazoan, Nematostella vectensis, revealing that the core components of the mammalian
ISR were present over 550 million years ago in the common ancestor of cnidarians and bilaterians.
Additionally, our lab has discovered a novel branch of the AAR pathway that regulates key tissue
protective signals. Using evolutionary conservation of this pathway in model organisms, I have identified
GCN1 as the branch point that links the signal generation components of the AAR pathway to
downstream therapeutic effects. I then used transcriptomic and protein interaction analyses to begin to
understand the scope of this pathway and identify key pathway regulators.
Description:
Funding for this research was provided by the National Science Foundation Graduate Research
Fellowship Program, Allied Bristol Life Sciences (to Malcolm Whitman), the WHOI Academic Programs
Office, and the WHOI Ocean Venture Fund.
Keywords:
Cells
;
Immune system
;
Amino acids
Repository Name:
Woods Hole Open Access Server
Type:
Thesis
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