Document text
Principal Investigator: Robert E Fleming
Organization: SAINT LOUIS UNIVERSITY
Fiscal Year: 2024
Award: $679,795
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
ABSTRACT
The overall goal of our proposal is to investigate how iron metabolism and erythropoietic activity are interrelated,
and the mechanisms whereby dysregulation in one contributes to pathophysiology in the other. Roles for the two
transferrin receptors in these processes is clear; however, little is understood regarding the signaling properties
of their ligand, transferrin. Transferrin has long been recognized to deliver iron by binding to receptor, transferrin
receptor 1 (TFR1), present on all cells. More recently, a homologous receptor, TFR2, has been identified almost
exclusively on bone marrow and liver cells where it serves as a sensor of iron supply and a regulator of
erythropoiesis. We generated mice in which one or other of the two iron binding sites (N and C) was mutated,
and unable to take in iron. We observed striking differences in the regulation of iron metabolism and
erythropoiesis between these mice, demonstrating that each of lobes of transferrin has distinct signaling
properties. We present in this proposal new data demonstrating significant improvement in a mouse model of
the human disease β-thalassemia when iron is specifically bound to the N but not C lobe. We now devote our
attention to the mechanisms by which the two transferrin lobes exert their effects. We also explore the potential
of increasing N lobe TF as a potential treatment approach in ineffective erythropoiesis.
Terms: <Affect><Affinity><Anemia><Attention><Autoregulation><B-thalassemia><BMP-6><BMP6><BMP6 gene><Basic Research><Basic Science><Binding><Binding Sites><Biologic Models><Biological Models><Blood Diseases><Blood Plasma><Blood Serum><Blood erythrocyte><Bone Marrow><Bone Marrow Reticuloendothelial System><CD71><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cells><Circulation><Clinical Sciences><Collaborations><Combining Site><Data><Disease><Disorder><Dysfunction><ECSF><EPOR><EPOR gene><Epoetin><Erythroblasts><Erythrocytes><Erythrocytic><Erythropoiesis><Erythropoietin><Erythropoietin Receptor Gene><Exhibits><Fe element><Fe metabolism><Functional disorder><Goals><HFE3><Health><Hematologic Diseases><Hematological Disease><Hematological Disorder><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hepc peptide><Hereditary hemochromatosis><Homeostasis><In Transferrin><Intracellular Communication and Signaling><Iron><KO mice><Knock-out Mice><Knockout Mice><Ligands><Liver><Liver Cells><Lobe><Marrow erythrocyte><Mediating><Mice><Mice Mammals><Model System><Molecular><Molecular Interaction><Murine><Mus><Mutate><Normoblasts><Nucleated Erythrocytes><Nucleated red blood cell><Nucleated red cell><Null Mouse><Participant><Patients><Physiologic><Physiological><Physiological Homeostasis><Physiopathology><Plasma><Plasma Proteins><Plasma Serum><Process><Production><Property><Publishing><Reactive Site><Receptor Protein><Receptor Signaling><Red Blood Cells><Red Cell><Regulation><Reporting><Reticuloendothelial System, Serum, Plasma><Role><Serum><Siderophilin><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Specificity><System><TFR gene><TFR protein><TFR1><TFR2><TFR2 gene><TFRC><TFRC gene><TRFR><Testing><Transferrin><Transferrin Receptor><Transferrin Receptor 1><VG1-Related Sequence><VGR1 Gene><age group><beta Thalassemia><biological signal transduction><blood corpuscles><blood disorder><blood treatment><bone morphogenetic protein 6><cell culture><cell cultures><cell type><deliver mRNA><deliver messenger RNA><delivery system for mRNA><derepression><diferric transferrin><disease model><disorder model><erythrocyte colony stimulating factor><erythroid development><falls><hematopoietin><hepatic body system><hepatic organ system><hepcidin><human disease><human model><improved><insight><iron metabolism><knock-down><knockdown><lipid based nanoparticle><lipid nanoparticle><lobes><mRNA delivery><meeting><meetings><messenger RNA delivery><model of human><mouse model><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nucleated RBCs><p-Thalassemia><pathophysiology><receptor><receptor mediated endocytosis><sensor><social role><therapeutic target><uptake><vgr-1 protein><β-thalassemia>