Mechanisms of Thyroid Hormone Action in Development

甲状腺激素(TH)对大多数器官系统的多种生理过程有着深远的影响，在维持基础代谢率和产热方面起着重要作用。在脊椎动物物种的发育过程中，TH对于分化和成熟的协调发展也很重要。甲状腺的主要分泌产物是甲状腺素(T4)，在外周组织中转化为3，5，3‘-三碘甲腺原氨酸(T3)，这是TH的生理活性形式。因此，脱碘酶对细胞内T_3水平的控制对T_3的作用是至关重要的。然而，个体脱碘酶的生理作用，特别是d1和d2，还没有明确的定义。通常认为，D1的功能主要是产生输出到血浆中的T3，而D2的活性被认为产生T3主要用于组织的局部使用。但这两种酶的独立功能的概念主要是基于间接证据，而且由于一些组织表达d1和d2的事实而变得复杂。这些酶的作用的实验证据一直是有限的，因为目前还没有已知的个别脱碘酶的特定药理抑制剂。我们的一般假设是，D1和D2提供了组织特异性的细胞内T3产生的适应，以响应内源性或环境对TH动态平衡的威胁。我们将使用小鼠基因敲除(KO)模型来验证这一假说，该模型缺乏D1或D2活性或两者兼而有之。在SA编号1中，将确定D2对TH活动的重要性，特别是对血浆TH水平对TSH的反馈调节以及对中枢神经系统的发育和功能的重要性。我们最近开发的D2KO小鼠将用于这些研究。在第2号SA中，将评估D1在经济中的生理作用，特别是它在甲状腺产生T3中的重要性以及它对外周T3产生的贡献。将为这些研究开发一种D1KO小鼠。在SA编号3中，将确定5‘-脱碘在TH作用中的总体重要性，以及在d1和d2的作用中是否存在功能重叠。通过杂交培育出一只同时缺乏D1D2基因的小鼠，并将该双D1KO模型的研究结果与D1KO和D2KO模型的研究结果进行比较。切除甲状腺的D1/D2KO小鼠也将提供一个很好的模型，在其中独立研究T3和T4的作用。综上所述，这些研究将为各种临床相关生理条件下TH代谢过程的重要性提供独特的、以前无法获得的见解。

Thyroid hormone (TH) has profound effects on a wide variety of physiological processes in most organ systems, and plays a major role in the maintenance of basal metabolic rate and thermogenesis. TH is also important for the coordinated progression of differentiation and maturation that occurs during development in vertebrate species. The principle secretory product of the thyroid gland is thyroxine (T4), which is converted in peripheral tissues to 3,5,3'-triiodothyronine (T3), the physiologically active form of TH. Thus it follows that the control of intracellular T3 levels by the deiodinases that generate, (types I (D1) and II (D2)) and degrade (type III (D3)) T3 is critical to TH action. However, the physiological roles of the individual deiodinases, in particular D1 and D2, have not been clearly defined. It is generally considered that the D1 functions primarily to generate T3 for export to the plasma, while the D2 activity is thought to generate T3 mainly for local use in tissues. But this concept of separate functions for the two enzymes is based largely on indirect evidence, and is complicated by the fact that some tissues express D1 as well as D2. Experimental proof of the roles of these enzymes has been limited because there are no known specific pharmacological inhibitors of the individual deiodinases. Our general hypothesis is that the D1 and the D2 provide for tissue-specific adaptations of intracellular T3 production in response to endogenous or environmental threats to TH homeostasis. We will test this hypothesis using mouse knock-out (KO) models that are deficient in either D1 or D2 activity or both. In SA number 1 the importance of D2 to TH action, in particular to the feedback regulation of TSH by plasma TH levels, and to the development and function of the CNS will be determined. The D2KO mouse that we have recently developed will be used for these studies. In SA number 2 the physiological role of the D1 in TH economy, in particular its importance in T3 production by the thyroid gland and its contribution to peripheral T3 production, will be assessed. A D1KO mouse will be developed for these studies. In SA number 3 the overall importance of 5'-deiodination in TH action, and whether there is functional overlap in the roles of the D1 and the D2 will be determined. A mouse deficient in both D1 and D2 will be developed by cross-breeding, and the results of studies using this double D1/D2KO model will be compared with those of the D1KO and the D2KO. The thyroidectomized D1/D2KO mouse will also provide an excellent model in which to study the effects of T3 and T4 independently. Taken together these studies will provide unique, previously unattainable insights into the significance of TH metabolic processes under a variety of clinically relevant physiological conditions.