[R01] Thyroid Hormone as a Key Regulator of Neurodevelopment during Early Life Iron Deficiency
Ente: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Scadenza: 2030-05-31
Importo max: 659.035 EUR
Paese: US
Descrizione
ABSTRACT: Globally, iron deficiency (ID) affects 40-50% of pregnant women, fetuses, and children. Fetal-
neonatal ID acutely impairs cognitive, motor and social development in children. More troubling from a public
health perspective is that neurobehavioral deficits persist despite neonatal iron treatment, causing increased risk
of cognitive and neuropsychiatric disorders into adulthood. In mice, hippocampal neuron-specific ID causes long-
term learning/memory neurocircuit dysfunction despite neonatal iron repletion, demonstrating the long-term
effects are due to neuronal iron loss during development. The neurobiological mechanisms by which developing
neurons metabolically adapt to early-life ID and that underly the long-term neurobehavioral deficits are unclear.
Neuronal development depends on both iron and thyroid hormone (TH) to meet the high energy demands of
rapid neuronal growth and maturation. Early-life TH deficiency (THD) causes similar neurodevelopmental
impairments as ID. Excess iron and TH both cause mitochondrial stress and are toxic. ID is an independent risk
factor for THD in pregnant women and children. However, the mechanistic basis for iron/TH interactions during
brain development are understudied. We previously showed that fetal-neonatal dietary ID reduces serum and
brain TH concentrations and impairs brain TH-regulated gene expression in neonatal rats. Reduced TH activity
in the neonatal iron-deficient brain is concerning as concurrent deficits in both iron and TH could be maladaptive
and cause a “double hit” to the developing brain and result in poorer outcome than either condition alone.
However, an alternative hypothesis is that reduced TH action may be adaptive and protect the developing
iron-deficient brain from metabolic stress by balancing the availability of iron, a critical metabolic substrate for
mitochondrial ATP production with TH-mediated metabolic/growth rate. In support of this “metabolic matching”
hypothesis, our published and preliminary data show that iron-deficient neurons have decreased mRNA levels
for TH-regulated genes despite normal TH availability, and increased oxidative stress signaling when TH
transcriptional activity is experimentally stimulated during ongoing ID. Understanding the neurobiological
mechanisms underlying this iron/TH interaction and whether ID-induced THD is adaptive or maladaptive to the
developing iron-deficient brain are critical gaps in knowledge that if addressed would lead to different clinical
management strategies for early-life ID. In Aim 1, we will determine how iron mechanistically controls neuronal
TH metabolism and activity during neuronal ID. Aim 2 will determine whether decreased TH activity is adaptive
or maladaptive for the metabolic and structural development of iron-deficient neurons. Aim 3 will translate our
competing “double-hit” and “metabolic matching” hypotheses to a clinically relevant rodent model of fetal-
neonatal IDA to determine whether TH treatment is
Istituzione: UNIVERSITY OF MINNESOTA
PI: Thomas W. Bastian
Progetto: 5R01HD117850-02
Settori: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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