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Principal Investigator: James F. Collins
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2020
Award: $511,395
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary
Iron is an essential nutrient for humans, yet excess iron is toxic. As such, iron overload and iron deficiency
result in severe homeostatic perturbations. Iron overload is most frequently associated with hereditary
hemochromatosis (HH), which afflicts ~1:250 adults in the U.S. Tissue iron accumulation in patients with HH
leads to arthritis, osteoporosis, liver damage and cancer, cardiomyopathy, diabetes mellitus, and impotence.
HH results from impaired production of the iron-regulatory hormone hepcidin (HEPC) or as a result of
mutations in the HAMP gene (encoding HEPC). HEPC limits intestinal iron absorption. Moreover, reduced
HEPC synthesis underlies the iron loading that typifies disorders of ineffective erythropoiesis (e.g. β-
thalassemia intermedia [βTI]). In HH and βTI, intestinal iron absorption is thus excessive. This leads to
pathological iron overload since humans cannot excrete excess iron. Regulation of intestinal iron absorption is
thus critical to properly control body iron levels. Dietary iron exists primarily as inorganic (or nonheme) iron.
Ferric (Fe3+) nonheme iron is first reduced to Fe2+, imported into duodenal enterocytes by divalent metal-ion
transporter 1 (DMT1), exported by ferroportin 1 (FPN1) and oxidized for binding to transferrin. DMT1 is the
primary intestinal iron importer under basal conditions, but the relative contribution of DMT1 to iron
accumulation in HH and βTI is unknown. In Aim 1, we will thus test the hypothesis that DMT1 is required
for iron loading in mouse models of HH (HEPC KO) and βTI (Hbbd3th; with a mutated β major globin [Hbb-
b1]) gene. We will thus generate HEPC and Hbb-b1 KO mice that are also lacking intestinal DMT1. We further
hypothesize that decreasing DMT1 expression will prevent iron loading in HH and βTI. Accordingly, we have
developed ginger nanoparticle-derived lipid vectors (GNLVs) which can deliver functional DMT1 siRNA to the
mouse duodenum in vivo (~40% reduction in DMT1 expression). In Aim 2, this GNLV delivery system will be
tested for its ability to prevent iron loading in rodent models of HH and βTI. Furthermore, iron deficiency (ID) is
also common in the U.S., afflicting ~8 million young women, and 700,000 infants. ID frequently occurs when
absorption of dietary iron does not meet the body’s demand. ID most commonly occurs as a consequence of
rapid growth, pregnancy, menstrual blood loss, malabsorptive disorders, gastric bypass surgery and chronic
inflammation. ID symptoms include anemia, impaired cognition, decreased immune response, and fatigue.
During ID, DMT1 increases Cu transport into duodenal enterocytes and emerging data demonstrates that
copper is critical to support iron repletion during states of deficiency. The mechanism that transforms DMT1
into a copper transporter is, however, unknown. Aim 3 will thus test the hypothesis that the DMT1 protein is
post-translationally modified during iron deficiency, allowing Cu transport. Plausible alternative hypotheses
may also be considered. Overall, this DMT1-focused investigation is likely to potentiate the development of
novel therapeutic and nutritional approaches to modulate intestinal iron absorption in at-risk individuals.
Terms: <21+ years old><Adult><Adult Human><Anemia><Arthritis><Autoregulation><Binding><Biochemical><Bleeding><Body Tissues><Cardiomyopathies><Chronic><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Common Rat Strains><Complex><Copper><Cu element><Data><Development><Diabetes Mellitus><Dietary Iron><Disease><Disorder><Disturbance in cognition><Duodenum><Endocrine Gland Secretion><Enterocytes><Epithelial><Epithelium><Epithelium Part><Erythropoiesis><Fatigue><Fe absorption><Fe deficiency><Fe element><Fe overload><Future><Gene Inactivation><Gene Silencing><Genes><Genetic Alteration><Genetic Change><Genetic defect><Gestation><Ginger><Globin><Goals><Hemorrhage><Hepatic Cancer><Hepc peptide><Hereditary><Hereditary hemochromatosis><Homeostasis><Hormones><Human><Hypoxia><Hypoxic><Immune response><Immunologic Technics><Immunologic Techniques><Immunological Technics><Immunological Techniques><Immunological response><Impaired cognition><Impairment><Impotence><Individual><Infant><Inflammation><Inherited><Injury to Liver><Intestinal><Intestines><Investigation><Ions><Iron><Iron Overload><KO mice><Knock-out Mice><Knockout Mice><Lack of Energy><Lipids><Maintenance><Malignant neoplasm of liver><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Mice><Mice Mammals><Modality><Modeling><Modern Man><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><Mutate><Mutation><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><Null Mouse><Nutrient><Nutritional><Osteoporosis><Oxides><Oxygen Deficiency><Pathologic><Patients><Physiologic><Physiological><Physiological Homeostasis><Play><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Pregnancy><Process><Production><Property><Protein Modification><Proteins><Rat><Rat Cell Line><Rats Mammals><Rattus><Regulation><Risk><Rodent Model><Role><Short interfering RNA><Siderophilin><Small Interfering RNA><Small Intestines><Structure><Symptoms><System><Technology><Testing><Therapeutic><Therapeutic Hormone><Tissues><Transferrin><Zingiber officinale><absorption><adolescent woman><adolescent women><adulthood><arthritic><bariatric surgery><base><basolateral membrane><beta thalassemia intermedia><blood loss><bowel><brush border membrane><clinical significance><clinically significant><cognitive dysfunction><cognitive loss><developmental><diabetes><dietary Fe><divalent metal><erythroid development><falls><ferroportin><ferroportin1 protein><gastric banding><gastric bypass surgery><genome mutation><hepatic damage><hepatic injury><hepcidin><host response><immunoresponse><implantable gastric stimulation banding><impotent><in vivo><insight><iron absorption><iron deficiency><liver cancer><liver damage><liver injury><mRNA Expression><malignant liver tumor><metal transporting protein 1><mortality><mouse model><murine model><myocardium disease><myocardium disorder><nano particle><nano-sized particle><nanoparticle><nanosized particle><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><nutritional approach><nutritious><obesity surgery><p-Globin><pre-clinical><preclinical><prevent><preventing><prophylactic><protein function><rapid growth><siRNA><siRNA delivery><small bowel><social role><solute carrier family 40 (iron-regulated transporter), member 1><stomach stapling><thalassemia intermedia><therapeutic target><transcriptional silencing><uptake><vector><weight loss surgery><young woman><β-thalassemia intermedia>