Copper, Iron and Thyroid Hormone Deficiency During Brain Development

描述（由申请人提供）：正常的大脑发育需要在精确的发育时间点向大脑提供适当水平的营养、激素和其他信号分子。例如，碘缺乏导致甲状腺激素（TH）产生减少和严重的发育异常。同样，大脑发育后期铜（Cu）和铁（Fe）缺乏导致大脑发育异常相似的紊乱。该研究计划的长期目标是了解发育中的大脑中Cu、Fe和TH的分子基础。为此，研究人员开发了一个模型，旨在确定与这三种缺陷相关的大脑发育异常的共同分子机制。最近的数据显示，TH的合成依赖于足够的铁水平。铁可能是TH合成酶甲状腺过氧化物酶正常功能所必需的。有趣的是，铜缺乏也与TH水平降低有关。调查人员的初步数据可能为后一种发现提供解释。他们观察到缺铜的啮齿动物会缺铁。这些动物体内的铁缺乏可能导致TH缺乏。因此，他们提出了以下假设：Cu和Fe缺乏导致脑TH水平降低。相关的TH水平降低有害地影响大脑发育，因此，有助于在缺铜和缺铁动物中观察到的大脑发育和功能紊乱。我们提出了三个具体目标来验证这些假设：目标1是评估脑发育晚期铜和铁缺乏对循环和脑TH水平的影响。目的2是比较脑发育晚期与Cu、Fe和TH缺乏相关的分子异常。目的3是评估TH的补充对脑发育后期与Cu和Fe缺乏相关的分子异常的影响。这些数据将揭示TH水平降低是否介导新生儿脑发育过程中Cu和Fe缺乏的一些病理生理效应。这些研究将进一步提供必要的初步数据，以开展旨在揭示每种成分对大脑发育和功能的精确贡献的机制研究。如果这些假设在模型动物研究中被证明是正确的，那么评估缺铜和缺铁婴儿的TH状态将是重要的，以确保在新生儿发育过程中获得足够的TH状态。这些发现可能具有直接和即时的临床影响，因为即使是大脑发育后期短暂的促甲状腺激素剥夺也与以后生活中认知能力下降有关。

DESCRIPTION (provided by applicant): 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.