Thyroid hormone is crucial to CNS development and function. A deficiency of thyroid hormone causes cretinism, a syndrome of severe impairment of physical and mental development. Relatively few genes in brain are known to be induced by thyroid hormone recently, we showed that one of these - Rhes (RasHomologous Enriched in Striatum, also called Dexras 2) - potently stimulates the brain iron transporter, or DMT1. The brain's iron requirement is relatively high. Intense brain metabolism and concomitant oxygen consumption depends upon a steady supply of iron to maintain cytochromes and mitochondrial function. Iron deficiency during pregnancy or postnatal life can result in brain maldevelopment. Administration of supplemental iron to children may not fully compensate for deprivation early in life: cognitive deficits are frequent in these youngsters. Conversely, iron excess can be neurotoxic, in part by favoring formation of reactive oxygen species (ROS). These observations indicate that iron transport into the CNS is a tightly ordered process that satisfies the need of the brain for this element without the imposition of a toxic burden. Our long-term goal is to elucidate the molecular basis and functional importance of iron brain trafficking. In this study, we will use molecular, cellular and biochemical approaches to characterize the function and regulation of Rhes. Our focus is to understand how this agents regulates iron transport and how this process affects neurotransmitter synthesis, which requires iron. Our research will provide insight into the mechanism(s) by which iron or thyroid deficiency hampers brain development. It also may lead to new strategies for the prevention of learning disabilities and for the management of children so affected.

Public Health Relevance

Iron is essential for proper brain function. We found that Rhes, a small GTPase, modulates iron trafficking in the brain. Rhes is induced by thyroid hormone, which plays an important role in neurodevelopment. Our project harnesses multiple biochemical and cellular techniques to gain mechanistic insight into how Rhes regulates iron homeostasis and contributes to the neuronal function, which will suggest novel avenues for therapeutic intervention.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Center Core Grants (P30)
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Special Emphasis Panel (ZHD1-MRG-C)
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Children's Hospital of Philadelphia
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