Iron homeostasis is a vital process that balances access to free iron to fuel physiological processes with iron storage to reduce the deleterious aspects of excess free iron. Dysfunctional iron homeostasis can lead to iron overload, in which excess free iron can promote cellular injury, ferroptosis, and eventual organ damage as a result. The cellular consequences of long-term iron overload including the cellular pathways that lead to pathological changes or those that may provide protection against damage are incompletely defined. Here, we use dietary and genetically engineered mouse models of iron overload combined with mass spectrometry-based quantitative proteomics to determine the iron overload liver proteome. We identify and quantify over 8,000 proteins representing the most in-depth iron overload proteome evaluation to date. Using bioinformatics, we identify conserved upregulated pathways including ‘response to oxidative stress’ and downregulated pathways including ‘steroid homeostasis.’ Furthermore, we identify an unexpected role for NCOA4, an autophagy adaptor that targets ferritin for autophagic degradation during iron deprivation, during iron overload. This work highlights the importance of further investigation into NCOA4 and its role in diseases of iron overload. / 2025-01-30T00:00:00Z

Central Nervous System (CNS) injury may lead to irreversible damage to cognitive and motor abilities when injured. This is due to the inability of axons to regenerate. This thesis focuses on two methods of promoting axonal regeneration: microtubule stabilization and upregulation of the intrinsic growth capacity of the neuron via the mechanistic target of rapamycin (mTOR) pathway. Both have shown promising results in potentially being a therapeutic treatment for CNS trauma. This research seeks to (1) test a combinatorial method of axonal regeneration utilizing both methods simultaneously and (2) compare microtubule stabilization and upregulation of the mTOR pathway as neuronal regeneration methods. Aim 1 serves to test the combinatorial treatment of Taxol, a microtubule stabilizer, and cRheb transfection, which upregulates the mTOR pathway, on neuronal cell cultures. Cells were cultured in either a growth-promoting substrate or a mix of growth-promoting and growth-inhibitory substrates. The results of this study revealed combinatorial treatment of 2DIV Taxol application with cRheb transfection as a promising treatment that yielded significantly greater axonal outgrowth than either treatment alone. Aim 2 serves to compare the two established methods of axonal regeneration in the scientific community. Based off of a meta-analysis, results of this aim indicate upregulation of mTOR is more effective at promoting axonal regeneration than microtubule stabilization.

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