A computational model to understand mouse iron physiology and diseases

The current paradigm in the field of mammalian iron biology states that body iron levels are determined by dietary iron absorption, not by iron excretion. Iron absorption is a highly regulated process influenced by iron levels and other factors. Iron excretion is believed to occur at a basal rate irrespective of iron levels and is associated with processes such as turnover of intestinal epithelium, blood loss, and exfoliation of dead skin. Here we explore iron excretion in a mouse model of iron excess due to inherited transferrin deficiency. Iron excess in this model is attributed to impaired regulation of iron absorption leading to excessive dietary iron uptake. Pharmacological correction of transferrin deficiency not only normalized iron absorption rates and halted progression of iron excess but also reversed body iron excess. Transferrin treatment did not alter the half-life of 59 Fe in mutant mice. 59 Fe-based studies indicated that most iron was excreted via the gastrointestinal tract and suggested that iron-loaded mutant mice had increased rates of iron excretion. Direct measurement of urinary iron levels agreed with 59 Fe-based predictions that urinary iron levels were increased in untreated mutant mice. Fecal ferritin levels were also increased in mutant mice relative to wild-type mice. Overall, these data suggest that mice have a significant capacity for iron excretion. We propose that further investigation into iron excretion is warranted in this and other models of perturbed iron homeostasis, as pharmacological targeting of iron excretion may represent a novel means of treatment for diseases of iron excess.

show abstract

“…A manuscript on the model is currently under review and a preprint version of the paper is available. 15…”

Section: Methodsmentioning

confidence: 99%

Gastrointestinal iron excretion and reversal of iron excess in a mouse model of inherited iron excess

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

A biomathematical model of human erythropoiesis and iron metabolism

Schirm

Scholz

2020

Sci Rep

View full text Add to dashboard Cite

Anaemia therapy or perisurgical support of erythropoiesis often require both, EPO and iron medication. However, excessive iron medication can result in iron overload and it is challenging to control haemoglobin levels in a desired range. To support this task, we develop a biomathematical model to simulate EPO- and iron medication in humans. We combine our previously established model of human erythropoiesis including comprehensive pharmacokinetic models of EPO applications with a newly developed model of iron metabolism including iron supplementation. Equations were derived by translating known biological mechanisms into ordinary differential equations. Qualitative model behaviour is studied in detail considering a variety of interventions such as bleeding, iron malnutrition and medication. The model can explain time courses of erythrocytes, reticulocytes, haemoglobin, haematocrit, red blood cells, EPO, serum iron, ferritin, transferrin saturation, and transferrin under a variety of scenarios including EPO and iron application into healthy volunteers or chemotherapy patients. Unknown model parameters were determined by fitting the predictions of the model to time series data from literature. We demonstrate how the model can be used to make predictions of untested therapy options such as cytotoxic chemotherapy supported by iron and EPO. Following our ultimate goal of establishing a model of anaemia treatment in chronic kidney disease, we aim at translating our model to this pathological condition in the near future.

show abstract

A computational model to understand mouse iron physiology and diseases

Cited by 2 publications

References 65 publications

Gastrointestinal iron excretion and reversal of iron excess in a mouse model of inherited iron excess

Gastrointestinal iron excretion and reversal of iron excess in a mouse model of inherited iron excess

A biomathematical model of human erythropoiesis and iron metabolism

Contact Info

Product

Resources

About