Title

Genetic Dissection of Local and Systemic Responses in States of Perturbed Iron Balance

Date of Award

Spring 2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Experimental Pathology

First Advisor

Finberg, Karin

Abstract

Iron balance is essential for health. Iron deficiency can impair multiple biological processes and, when severe, restrict red blood cell production, resulting in iron deficiency anemia. Excess iron, on the other hand, can catalyze the generation of harmful reactive oxygen species, leading to tissue damage and organ failure. Because at least 1 billion people worldwide exhibit altered iron balance, understanding iron pathophysiology has broad implications for global health. In this thesis, I use genetic approaches in mouse models and tissue culture systems to dissect local and systemic responses in states of perturbed iron balance. The first part of this thesis defines local responses in the liver, the major iron depot of the body, after blood loss. We showed that NCOA4 (nuclear receptor coactivator 4), a widely expressed intracellular protein, mediates the mobilization of hepatic iron stores after blood loss. Additionally, we provided evidence that the expression of NCOA4 is regulated by hypoxia inducible factor (HIF) in cells of hepatic origin. Because HIF stability is regulated by both oxygen and iron levels, our findings suggest a novel mechanism by which hypoxia and iron deficiency may modulate NCOA4 expression to impact iron homeostasis. The second part of my thesis work focuses on systemic responses during iron deficiency. We showed that mice with chronic iron deficiency anemia exhibit elevated circulatory levels of FGF23 (fibroblast growth factor 23), a hormone that regulates systemic phosphate homeostasis. By utilizing a genetic mouse model that allows us to track sites of FGF23 production, we revealed that a subset of cells in the bone marrow have increased Fgf23 expression in iron deficiency anemia. As prior studies have indicated that low serum iron levels are associated with increased FGF23 levels in humans, our study may have implications for understanding FGF23 regulation in clinical states with dysregulated iron homeostasis. In summary, this body of work elucidates specific local and systemic responses in states of perturbed iron balance. By expanding our understanding of iron pathophysiology, knowledge gained from these studies has relevance to the development of novel therapies for humans patients with altered iron balance.

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