Browsing by Author "Andrews, Nancy C"
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Item Open Access Characterization of the Role of Transferrin receptor 1 (Tfr1) in the Intestinal Epithelium, Pancreas and Skin(2015) Chen, AlanTransferrin receptor 1 (Tfr1) serves as a receptor for transferrin, an iron-binding protein in the blood, in its canonical role of iron assimilation. Tfr1 is expressed ubiquitously in many tissues and is believed to be required for iron uptake by most cells.
The Tfr1 global knockout mouse highlights the requirement for Tfr1 in erythrocyte precursors. The erythron is the tissue with the highest iron requirement, to enable hemoglobin production. Tfr1-null embryos die by embryonic day 12.5 with anemia, which has been assumed to cause lethality of the knockout mice. Due to the embryonic lethality of the mice, the role of Tfr1 has not been well characterized in other tissues in vivo. This thesis examines the role of Tfr1 in other tissues through the generation and characterization of conditional knockout mouse models of Tfr1 deletion in the intestinal epithelium, pancreas, and skin.
Tfr1 is expressed on the basolateral surface of proliferating cells in the intestinal epithelium. Deletion of Tfr1 specifically in the intestinal epithelium resulted in the loss of intestinal epithelial homeostasis, loss of proliferation, lipid accumulation, gene expression indicating epithelial to mesenchymal transition of intestinal epithelial cells, and early neonatal lethality. These phenotypes were mostly alleviated by forced expression of a mutant Tfr1 allele which is unable to bind to iron-loaded transferrin, suggesting that Tfr1 has a novel role independent of its canonical iron-assimilatory ability.
Deletion of Tfr1 in the pancreas resulted in juvenile death due to perturbed homeostasis of both endocrine and exocrine tissues, resulting in symptoms associated with pancreatitis and diabetes. No diabetic phenotype was detected in the conditional knockout mouse model of Tfr1 deletion specifically in β-cells, suggesting that the primary effect of the loss of Tfr1 was limited to the exocrine tissue.
Deletion of Tfr1 in the epidermis of the skin caused neonatal lethality with abnormal hair follicle morphology and a significant reduction in dermal adipocytes.
These results indicate that the loss of Tfr1 has pleiotropic effects, depending on the cell type affected. Furthermore, Tfr1 appears to have non-canonical functions in the intestinal epithelium, a novel discovery.
Item Open Access Control of Systemic Iron Homeostasis by the 3' Iron-Responsive Element of Divalent Metal Transporter 1 in Mice.(HemaSphere, 2020-10) Tybl, Elisabeth; Gunshin, Hiromi; Gupta, Sanjay; Barrientos, Tomasa; Bonadonna, Michael; Celma Nos, Ferran; Palais, Gael; Karim, Zoubida; Sanchez, Mayka; Andrews, Nancy C; Galy, BrunoSupplemental Digital Content is available in the text.Item Open Access Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice.(J Clin Invest, 2010-12) Gardenghi, Sara; Ramos, Pedro; Marongiu, Maria Franca; Melchiori, Luca; Breda, Laura; Guy, Ella; Muirhead, Kristen; Rao, Niva; Roy, Cindy N; Andrews, Nancy C; Nemeth, Elizabeta; Follenzi, Antonia; An, Xiuli; Mohandas, Narla; Ginzburg, Yelena; Rachmilewitz, Eliezer A; Giardina, Patricia J; Grady, Robert W; Rivella, StefanoExcessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. Serial analyses of β-thalassemic mice indicate that while hemoglobin levels decrease over time, the concentration of iron in the liver, spleen, and kidneys markedly increases. Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Patients with β-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis and that increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. Here we demonstrate that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. These data led us to suggest that therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.Item Open Access Lack of Transferrin Receptor 1 in the Heart Causes Lethal Cardiomyopathy and Disruption of Mitophagy in Mice(2015) Xu, WenjingIron is an essential nutrient involved in numerous cellular functions and tightly regulated within cells. It is extremely important to maintain both systemic and intracellular iron homeostasis by orchestrating iron uptake, storage, utilization and export. Many human diseases are associated with disruption of iron homeostasis. Both iron overload and iron deficiency have been associated with cardiomyopathy and heart failure, but the molecular details of cardiac iron utilization are incompletely understood. Although it was known that transferrin receptor 1 (Tfr1) is responsible for iron uptake in erythroid precursors, its role in other tissues, and other possible roles, have not been studied in detail. We hypothesized that Tfr1 might play a role in cardiac iron uptake and used gene targeting to examine the role of Tfr1 in the heart in vivo. Tfr1 was deleted specifically in cardiomyocytes, and loss of Tfr1 caused iron deficiency in the heart. Surprisingly, we found that decreased iron was associated with severe cardiac metabolic consequences. Mice lacking Tfr1 in the heart died in the second week of life, with cardiomegaly, poor cardiac function, failure of mitochondrial respiration and ineffective mitophagy. The phenotype could only be rescued by aggressive and ongoing iron therapy, but it was ameliorated by either a mutant Tfr1 allele that does not bind transferrin or administration of nicotinamide riboside, an NAD precursor.
In summary, our study found that Tfr1 plays a primary role in uptake of Tf-bound iron in the heart, and yet may have other iron-independent functions in autophagy. Our results showed that iron is critical for the normal cellular metabolism, mitochondrial respiration and mitophagy in the heart. Our findings underscore the importance of both Tfr1 and iron in the heart and provide mechanistic evidence for iron therapy in heart failure patients. By elucidating the processes iron participates in the heart and the consequences of cardiac iron deficiency, our study may inform the identification of new therapeutic targets for heart failure. Finally, we found that NR prolonged the lifespan of mice with cardiac iron deficiency, suggesting possible benefit in treating heart failure accompanied by iron deficiency.