Thesis: Ph. D., Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Department of Biology; and the Woods Hole Oceanographic Institution), 2018. / Cataloged from PDF version of thesis. / Includes bibliographical references. / 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-eIF2x 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 eIF2a, 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. / 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 / by Maja Lena Edenius. / Ph. D.
| Identifer | oai:union.ndltd.org:MIT/oai:dspace.mit.edu:1721.1/115682 |
| Date | January 2018 |
| Creators | Edenius, Maja Lena |
| Contributors | Malcolm Whitman and Mark Hahn., Woods Hole Oceanographic Institution., Joint Program in Oceanography/Applied Ocean Science and Engineering., Massachusetts Institute of Technology. Department of Biology., Woods Hole Oceanographic Institution. |
| Publisher | Massachusetts Institute of Technology |
| Source Sets | M.I.T. Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 102 pages, application/pdf |
| Rights | MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission., http://dspace.mit.edu/handle/1721.1/7582 |
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