Thyroid Hormone Action

该项目的长期目标是了解甲状腺激素作用的分子机制。 甲状腺激素是甲状腺发育和动态平衡以及甲状腺异常的重要调节因素。 状态与许多人类疾病有关，从癌症到出生缺陷再到新陈代谢障碍。 甲状腺素(T4)是甲状腺分泌的甲状腺激素的主要形式，而T4是 通过酶促脱碘作用代谢成活性激素T3。T3对甲状腺转录的调节作用 通过与核甲状腺激素受体结合并激活激素反应基因。然而，在那里 甲状腺激素的许多作用发生得比转录调节的时间要快得多， 而这些快速效应的分子机制尚不清楚。这项研究计划是围绕 快速甲状腺激素信号传递与T4的一种新代谢物有关的假说 有别于T3。这种新的代谢物存在的实验支持了这一假说。 在组织中，以及当代谢产物被注射到组织中时诱导快速生理反应 活着。此外，这种T4代谢物是一种新发现的孤儿G蛋白偶联的有效激动剂 与生物胺GPCRs家族相关的受体(GPCR)。这项研究计划旨在进一步 探索这一甲状腺激素信号的新途径。具体目标1涉及化学修饰 代谢物，以描述对gpr激活重要的结构特征。具体目标2是一项研究 了解负责产生快速作用的T4代谢物的酶学。具体目标3 涉及不同亚型的分离、表达和药理学特性 对代谢物有反应的gpr。具体目标4是一种检查不同组织的方法 代谢物的存在并进行定量分析。具体目标5是开发一种化学物质的计划 代谢产物的拮抗剂，这将有助于研究这种新的甲状腺激素的体内生物学 信号通路。

The long-term objective of this project is to understand the molecular mechanisms of thyroid hormone action. Thyroid hormone is an important regulator of development and homeostasis, and abnormalities in thyroid status correlate with many human diseases ranging from cancer to birth defects to metabolic disorders. Thyroxine (T4) is the major form of thyroid hormone that is secreted from the thyroid gland, and T4 is metabolized to the active hormone T3 by enzymatic deiodination. T3 regulates the transcription of thyroid hormone responsive genes by binding to and activating nuclear thyroid hormone receptors. However, there are many effects of thyroid hormone that occur much faster than the timescale of transcriptional regulation, and the molecular mechanisms of these rapid effects are unknown. This research plan is constructed around the hypothesis that rapid thyroid hormone signaling involves a novel metabolite of T4 that is chemically distinct from T3. This hypothesis is supported by experiments showing the existence of this novel metabolite in tissue, as well as the induction of rapid physiological responses when the metabolite is administered in vivo. In addition, this T4 metabolite is a potent agonist of a newly discovered orphan G protein-coupled receptor (GPCR) related to the family of a biogenic amine GPCRs. This research plan seeks to further explore this novel pathway of thyroid hormone signaling. Specific aim 1 involves chemical modification of the metabolite to delineate the structural features important to GPCR activation. Specific aim 2 is a study to understand the enzymology responsible for generating the rapid-acting T4 metabolite. Specific aim 3 involves the isolation, expression, and pharmacological characterization of the different subtypes of the GPCR that responds to the metabolite. Specific aim 4 is an approach to examine different tissues for the presence of the metabolite and perform quantitative analysis. Specific aim 5 is a plan to develop a chemical antagonist of the metabolite that will be useful for studying the in vivo biology of this new thyroid hormone signaling pathway.