Thyroid Hormone Action

甲状腺激素作用

• 批准号: 7273716
• 负责人: THOMAS Sterling SCANLAN
• 金额: $ 31.19万
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7273716
• 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

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.

描述（由申请人提供）：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体内平衡的重要调节剂，甲状腺状态的异常与许多人类疾病相关，从癌症到出生缺陷到代谢紊乱。甲状腺素（T4）是甲状腺分泌的甲状腺激素的主要形式，T4通过酶促脱碘代谢为活性激素T3。T3通过结合并激活核甲状腺激素受体来调节甲状腺激素应答基因的转录。然而，甲状腺激素的许多作用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。这项研究计划是围绕一个假设，即快速甲状腺激素信号涉及一种新的T4代谢产物，其化学性质与T3不同。该假设得到了实验的支持，这些实验显示组织中存在这种新型代谢物，以及当体内给予代谢物时诱导快速生理反应。此外，这种T4代谢物是一种新发现的孤儿G蛋白偶联受体（GPCR）的强效激动剂，该受体与生物胺GPCR家族相关。这项研究计划旨在进一步探索这种甲状腺激素信号传导的新途径。具体目标1涉及代谢物的化学修饰，以描述对GPCR活化重要的结构特征。具体目标2是一项研究，以了解负责产生速效T4代谢产物的酶学。具体目标3涉及对代谢物有反应的GPCR不同亚型的分离、表达和药理学表征。具体目标4是检查不同组织中代谢物的存在并进行定量分析的方法。具体目标5是开发代谢物的化学拮抗剂的计划，该化学拮抗剂将用于研究这种新的甲状腺激素信号传导途径的体内生物学。