Thyroid Hormone Action

甲状腺激素作用

• 批准号: 7574689
• 负责人: THOMAS Sterling SCANLAN
• 金额: $ 2.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7574689
• 关键词: 3-iodothyronamine; Affinity; Agonist; Amino Acids; Animals; Aromatic Amino Acids; Binding; Biogenic Amines; Biological Assay; Biological Preservation; Biology; Body Temperature; Brain; Cardiac; Cardiac Output; Catecholamines; Chemicals; Congenital Abnormality; Coupling; Data; Decarboxylation; Development; Dopamine; Dose; Drops; Endocrinology; Enzymatic Biochemistry; Enzymes; Equilibrium; Essential Amino Acids; Family; Fever; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Genetic Transcription; Heart; Homeostasis; Hormone Responsive; Hormones; Hour; Hyperthyroidism; Ligands; Malignant Neoplasms; Mediating; Membrane; Metabolic Diseases; Modification; Molecular; Mus; Nuclear; Nuclear Receptors; Numbers; Pathway interactions; Physiological; Preparation; Process; Range; Rattus; Receptor Activation; Regulation; Research; Research Personnel; Rodent; Serotonin; Signal Pathway; Signal Transduction; Structure; Tars; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Thyroxine; Tissues; Transcriptional Regulation; Upper arm; Work; day; deiodination; design; hemodynamics; human GPRC5C protein; human disease; hyperthermia treatment; in vivo; induced hypothermia; natural hypothermia; non-genomic; novel; programs; receptor; research study; response; thyronamine

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.

该项目的长期目标是了解甲状腺激素作用的分子机制。 甲状腺激素是发育和体内平衡的重要调节剂，甲状腺异常 状态与许多人类疾病相关，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是 通过酶促脱碘代谢为活性激素 T3。 T3 调节甲状腺转录 通过结合并激活核甲状腺激素受体来调节激素反应基因。然而，有 甲状腺激素的许多作用发生得比转录调节的时间尺度快得多， 这些快速作用的分子机制尚不清楚。本研究计划围绕 假设快速甲状腺激素信号传导涉及 T4 的一种新型代谢物，该代谢物的化学性质是 与T3不同。这一假设得到了表明这种新型代谢物存在的实验的支持 在组织中，以及当代谢物施用在组织中时诱导快速的生理反应 体内。此外，这种 T4 代谢物是新发现的孤儿 G 蛋白偶联的有效激动剂 受体（GPCR）与生物胺 GPCR 家族相关。该研究计划旨在进一步 探索甲状腺激素信号传导的这一新途径。具体目标 1 涉及化学修饰 代谢物来描绘对 GPCR 激活重要的结构特征。具体目标 2 是一项研究 了解负责产生速效 T4 代谢物的酶学。具体目标3 涉及不同亚型的分离、表达和药理学特征 对代谢物做出反应的 GPCR。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 是开发化学品的计划 代谢物的拮抗剂，可用于研究这种新甲状腺激素的体内生物学 信号通路。