Yelena Z Ginzburg, MD

One main direction of the laboratory is to study the pathophysiology of iron overload and its regulation of / by erythropoiesis in iron loading anemias (e.g. β-thalassemia) using several mouse models (th1/th1 and th3/+). We hypothesized that transferrin, the main iron delivery molecule, provides an important compensatory mechanism in diseases of concurrent anemia and iron overload, demonstrating that exogenous transferrin ameliorates all erythroid- and iron-related pathology in th1/th1 mice [Li Nat Med 2010; Liu Blood 2013]. Evaluating hepcidin as a therapeutic tool [Gardenghi JCI 2010; Casu Blood 2016], its regulation in th3/+ mice in general [Parrow Blood 2012], and after treatment with transferrin [Chen haematol 2016], have further shed light on the mechanisms involved in exogenous transferrin’s effect on erythroid regulation of iron metabolism. Transferrin-bound iron binding to transferrin receptor 1 (TfR1) is essential for cellular iron delivery during erythropoiesis. We hypothesize that overexpressed TfR1 may play a regulatory role contributing to iron overload and anemia in β-thalassemic mice and that the beneficial effect of exogenous transferrin is mediated via decreased TfR1 expression. We previously demonstrated that apoTf-treated th1/th1 mice exhibit more iron restricted erythropoiesis, decreased transferrin saturation [Li Nat Med 2010], and less liver iron deposition [Chen haematol 2016]. Similar findings were evident in th3/+ mice [Gelderman haematol 2015]. Soluble TfR1, increased in β-thalassemic humans [Origa haematol 2007] and mice [Richardson Biochim Biophys Acta 1997], is decreased after treatment with apoTf in th1/th1 mice [Liu Blood 2013]. The current R01 funded work is aimed at exploring how TfR1 is involved in regulation of erythroid differentiation and enucleation in β-thalassemia (R01 NIDDK; PI: Ginzburg).