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Dissertation
A cellular approach to understanding and treating Gulf War Illness
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2021
DOI:
https://doi.org/10.17918/00000575
Abstract
Gulf War Illness (GWI) is a chronic multisystem disorder with prominent cognitive impairments that affects approximately 30% of the nearly 700,000 U.S. veterans of the 1991 Gulf War. GWI is caused by low level exposure to organophosphate pesticides and nerve agents in combination with the physical stressors of the battlefield, thus implicating non-cholinergic, novel biological targets. To elucidate the mechanistic basis of the cognitive symptoms, we differentiated human induced pluripotent stem cells (hiPSCs) derived from GW veterans with and without GWI into forebrain glutamatergic neurons and forebrain cerebral organoids, and exposed them to a GW relevant toxicant regimen of cortisol (to mimic battlefield stress) and the sarin analog diisopropyl fluorophosphate. We observed numerous cellular changes, including elevations in the levels and pathological phosphorylation of tau, reductions in microtubule acetylation and neuronal activity, and alterations in mitochondrial health, dynamics, and transport. In addition, we observed increased astrocyte reactivity and impaired neurogenesis in the organoids. Many of the results suggest that veterans who acquired GWI might be predisposed to a heightened response to the toxicant regimen. Adult rats exposed to a similar toxicant regimen (with corticosterone instead of cortisol) displayed a mild learning and memory deficit, as well as tau pathology selectively in the CA3 region of the hippocampus. Together, these results demonstrate that veteran-derived cell lines can be used as new model systems in coordination with rodent models to define the cellular responses that underlie the cognitive symptoms of GWI, and to screen for effective therapies for veterans with GWI.
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Details
- Title
- A cellular approach to understanding and treating Gulf War Illness
- Creators
- Philip Langdon Yates
- Contributors
- Peter W. Baas (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xii, 194 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 991014972849104721