Normal brain development requires appropriate levels of nutrients, hormones, and other signaling molecules presented to the brain at precise developmental timepoints. For example, iodine deficiency results in reduced thyroid hormone (TH) production and severe developmental abnormalities. Similarly, copper (Cu) and iron (Fe) deficiencies during late brain development result in strikingly similar derangements in brain development. The long-term goal of the proposed research program is to understand the molecular basis of Cu, Fe, and TH action in the developing brain. To this end, the investigators have developed a model that seeks to identify a shared molecular mechanism causative of the aberrancies in brain development associated with these three deficiencies. Recent data have revealed that TH synthesis is reliant on adequate Fe levels. Fe is likely required for normal function of the TH synthesizing enzyme thyroid peroxidase. Interestingly, Cu deficiency is also associated with reduced TH levels. The investigators' preliminary data may provide an explanation for this latter finding. They have observed that Cu deficient rodents become Fe deficient. The Fe deficiency in these animals likely results in TH deficiency. Thus, they have formulated the following hypothesis: that Cu and Fe deficiencies lead to reductions in brain TH levels. The associated reduction in TH levels deleteriously affects brain development and therefore, contributes to the derangements in brain development and function observed in Cu and Fe deficient animals.
Three specific aims are proposed to test these hypotheses:
Aim 1 is to assess the effects of Cu and Fe deficiency during late brain development on circulating and brain TH levels.
Aim 2 is to compare the molecular abnormalities associated with Cu, Fe, and TH deficiencies during late brain development.
Aim 3 is to assess the effects of TH repletion on molecular abnormalities associated with Cu and Fe deficiencies during late brain development. These data will reveal whether reduced TH levels mediate some of the pathophysiological effects of Cu and Fe deficiency during neonatal brain development. These studies will further provide the preliminary data necessary to conduct mechanistic studies designed to reveal the precise contributions of each constituent towards brain development and function. If the hypotheses prove correct in model animal studies, it will be important to assess the TH status of Cu and Fe deficient infants to ensure that adequate TH status is obtained during neonatal development. Such findings may have a direct and immediate clinical impact, as even transient TH deprivation during late brain development is associated with reduced cognitive abilities later in life. ? ? ?
