Thyroid Hormone Action

描述(由申请者提供)：本项目的长期目标是了解甲状腺激素作用的分子机制。甲状腺激素是发育和稳态的重要调节因素，甲状腺状态的异常与许多人类疾病有关，从癌症到出生缺陷再到代谢紊乱。甲状腺素(T4)是甲状腺分泌的甲状腺激素的主要形式，T4通过酶脱碘作用代谢为活性激素T3。T3通过结合和激活甲状腺激素核受体来调节甲状腺激素反应基因的转录。然而，有许多甲状腺激素的作用发生得比转录调节的时间快得多，而且这些快速作用的分子机制尚不清楚。这项研究计划是围绕这样的假设构建的，即快速甲状腺激素信号涉及T4的一种新的代谢物，该代谢物在化学上与T3不同。这一假设得到了实验的支持，实验表明这种新的代谢物在组织中的存在，以及当代谢物在体内给药时诱导快速生理反应。此外，这种T4代谢物是新发现的与生物胺GPCRs家族相关的孤儿G蛋白偶联受体(GPCRs)的有效激动剂。这项研究计划试图进一步探索甲状腺激素信号的这一新途径。具体目标1涉及对代谢物的化学修饰，以描述对GPCR激活重要的结构特征。特定目标2是一项研究，旨在了解负责产生快速作用的T4代谢物的酶学。具体目标3涉及对代谢物作出反应的不同亚型的gpr的分离、表达和药理学特征。具体目标4是一种检查不同组织中是否存在代谢物并进行定量分析的方法。具体目标5是开发一种代谢物的化学拮抗剂，这将有助于研究这一新的甲状腺激素信号通路的体内生物学。

DESCRIPTION (provided by applicant): 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.