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Principal Investigator: Nicolae Valentin David
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $656,337
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
Intact fibroblast growth factor 23 (iFGF23) is a phosphate regulating hormone secreted by bone. In chronic
kidney disease (CKD), increased Fgf23 transcription is associated with cardiovascular mortality, disturbed iron
metabolism and anemia. Fgf23 transcription is physiologically coupled to FGF23 cleavage by Furin resulting in
secretion of iFGF23, carboxy terminal (Cter) and amino terminal (Nter) FGF23 peptides. The well-established
function of iFGF23 is to maintain normal phosphate homeostasis by targeting the kidney but there is emerging
evidence supporting extra-renal FGF23 targets which might be the result of increased Cter- and Nter-FGF23
signaling. Novel approaches to reduce FGF23-associated adverse outcomes in CKD are desperately needed
but current therapies are suboptimal due to lack of understanding of the role of FGF23 peptides.
In preliminary data we show that in addition to iFGF23, FGF23 peptides are secreted by bone and extraosseous
sources, including erythroid cells, in CKD. We also show that these peptides display novel physiological
functions. Cter-FGF23 peptides suppress the secretion of the hepatic iron regulatory hormone, hepcidin, leading
to increased circulating iron. Nter-FGF23 peptides are not released in the circulation when FGF23 is expressed
in bone, but in iron deficient animals and patients and mice with CKD, FGF23 production by erythroid cells
contribute to increased circulating Nter-FGF23 levels. When elevated, Nter-FGF23 reduces the secretion of
erythropoietin, inhibits erythropoiesis and induces left ventricular hypertrophy (LVH). These observations support
important new roles of FGF23 peptides, and a functional role for the coupled regulation of Fgf23 transcription
and iFGF23 cleavage. In Aim 1, we will establish the physiological and pathological role of Cter-FGF23 peptides
in iron metabolism. Using multiple genetic mouse models, we will delete and overexpress Fgf23 and Cter-Fgf23
in bone, to test whether Cter-FGF23 peptides generated from increased FGF23 cleavage, protect mice against
overt hypoferremia by uniquely limiting hepcidin secretion in models of high (inflammation and iron overload) or
low (iron deficiency) endogenous hepcidin and compare these effects to exogenous hepcidin administration. We
will further test the therapeutic potential of genetic and pharmacologic Cter-FGF23 supplementation in two
mouse models of CKD and assess the onset and development of iron deficiency anemia. In Aim 2, we will use
the genetic overexpression and pharmacologic administration of FGF23 and Nter-FGF23 in osteocytes and
erythroid cells, in vivo and in vitro, to investigate the direct role of iFGF23, Nter-FGF23 and FGFR signaling in
the inhibition of erythropoiesis, and their indirect role by regulating erythropoietin (EPO) production in kidney and
liver. We will further investigate whether erythroid-produced Nter-FGF23 peptides contribute to LVH in mice with
CKD and test the direct hypertrophic effects of Nter-FGF23 in cardiomyocytes cultures. This project will
contribute to new insights into the molecular functions of FGF23 and support our ultimate goal of developing
novel therapeutic approaches to improve adverse outcomes associated with excess FGF23.
Terms: <Acute><Anemia><Animals><Autoregulation><B abortus><B. abortus><Bilateral><Binding><Bioavailability><Biological Availability><Brucella abortus><Brucella melitensis biovar abortus><C-terminal><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Maturation><Cell Signaling><Cell secretion><Cellular Secretion><Chronic><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Circulation><Consensus><Coupled><Coupling><Data><Development><Diet><Disease><Disease Outcome><Disorder><ECSF><Endocrine Gland Secretion><Epoetin><Erythroid><Erythroid Cells><Erythropoiesis><Erythropoietin><FGF Receptors><FGF-R><FGF23 gene product><FGFR><Fe deficiency><Fe element><Fe metabolism><Fe overload><Fibroblast Growth Factor Receptor Family><Fibroblast Growth Factor Receptors><Gene Transcription><General Population><General Public><Genetic><Genetic Transcription><Goals><Heart Hypertrophy><Heart Muscle Cells><Heart Vascular><Heart myocyte><Hepatic><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hepc peptide><Homeostasis><Hormone secretion><Hormones><Impairment><In Vitro><Inflammation><Inflammatory><Interleukins><Intermediary Metabolism><Intracellular Communication and Signaling><Iron><Iron Overload><Iron deficiency anemia><Ischemia-Reperfusion Injury><Kidney><Kidney Urinary System><Lead><Left Ventricular Hypertrophy><Length><Liver><Liver Cells><Mediating><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modeling><Molecular><Molecular Interaction><Morphology><Murine><Mus><Muscle Cells><Myocytes><N-terminal><NH2-terminal><Operative Procedures><Operative Surgical Procedures><Osteoblasts><Osteocytes><Outcome><Pathologic><Patients><Pb element><Peptides><Phosphates><Physiologic><Physiologic Availability><Physiological><Physiological Homeostasis><Production><Proteins><RNA Expression><Regulation><Renal function><Reperfusion Damage><Reperfusion Injury><Resistance><Role><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Source><Supplementation><Surgical><Surgical Interventions><Surgical Models><Surgical Procedure><Testing><Therapeutic><Therapeutic Hormone><Transcription><Ventricular><adverse consequence><adverse outcome><biological signal transduction><bone><cardiac hypertrophy><cardiomyocyte><cardiovascular disorder><cellular differentiation><chronic kidney disease><circulatory system><dentin matrix protein 1><design><designing><developmental><diets><disease model><disorder model><dmp1><erythrocyte colony stimulating factor><erythroid development><erythroid differentiation><fibroblast growth factor 23><heavy metal Pb><heavy metal lead><hematopoietin><hepatic body system><hepatic organ system><hepcidin><hormonal secretion><improved><improved outcome><in vivo><innovate><innovation><innovative><inorganic phosphate><insight><iron deficiency><iron metabolism><kidney function><mortality><mouse model><murine model><neonatal mice><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><overexpress><overexpression><pharmacologic><prevent><preventing><renal><resistant><response><social role><surgery><therapeutic evaluation><therapeutic testing>