Molecular Basis of Thyroid in Hormone Action in Brain Development

PI：丹佛，R.IBN-9724080脊椎动物大脑的正常发育需要甲状腺激素(TH)。胎儿时期激素不足会导致神经发育的严重缺陷(例如，人类的克汀病)。在全球范围内，先天性甲状腺功能减退症是最普遍和最有害的人类健康问题之一，在世界某些地区导致整个人口的智力受损和身体发育迟缓。除了缺碘引起的甲状腺功能减退外，最近关于各种工业生产的化合物对甲状腺轴的干扰作用的报告表明，环境污染物可能对人类和野生动物的发育过程产生深远的负面影响。这项拟议的研究旨在了解TH在脊椎动物中枢神经系统(CNS)发育中作用的分子基础。非洲爪蛙非洲爪蛙的蝌蚪将被用来研究TH诱导的神经发育，并在中枢神经系统中克隆TH靶基因。这个模型对于理解胚胎后大脑发育是非常宝贵的，因为它提供了进入所有发育阶段的容易途径，而且青蛙和包括人类在内的其他脊椎动物的基本神经发育过程类似。其主要目的是：1)了解TH受体如何将激素信号转导到细胞核，从而导致基因表达的变化；2)了解中枢神经系统中TH靶基因的结构和功能。

PI: Denver, R. IBN-9724080 Normal development of the vertebrate brain requires thyroid hormone (TH). Insufficient amounts of hormone during fetal life results in severe defects in neural development (e.g., cretinism in humans). On a global scale, congenital hypothyroidism is one of the most pervasive and detrimental human health problems, resulting in entire populations of mentally impaired ad physically stunted individuals in certain areas of the world. In addition to hypothyroidism caused by iodine deficiency, recent reports of disruptive effects on the thyroid axis of various industrially-produced compounds suggest the possibility for profound negative effects of environmental pollutants on developmental processes of humans and wildlife. The proposed research aims to understand the molecular basis of TH action on the development of the vertebrate central nervous system (CNS). Tadpoles of the African clawed frog, Xenopus laevis will be used to study TH-induced neural development and to clone TH-target genes in the CNS. This model in invaluable for understanding post-embryonic brain development since it affords easy access to all stages of development, and the basic neurodevelopmental processes are similar in frogs and other vertebrate animals including humans. The primary objectives are to: 1) understand how TH receptors transduce the hormonal signal to the cell nucleus resulting in changes in gene expression, and , 2) understand the structure and function of TH target genes in the CNS.