Thyroid Hormone Action

甲状腺激素作用

• 批准号: 8501426
• 负责人: THOMAS Sterling SCANLAN
• 金额: $ 33.07万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501426
• 关键词: 3-iodothyronamine; Acute; Adult; Affinity; Agonist; Appetite Depressants; Binding; Binding Proteins; Biogenic Amines; Biological; Blood Circulation; Body Temperature; Body Weight; Body Weight decreased; Bradycardia; Brain; Burn injury; Carbohydrates; Cardiac; Catecholamines; Cell Nucleus; Cell membrane; Chemicals; Child; Chronic; Critical Care; Development; Diet; Disease; Dopamine; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Endocrine system; Energy Intake; Energy Metabolism; Ensure; Equilibrium; Fatty acid glycerol esters; Feeding behaviors; G-Protein-Coupled Receptors; Goals; Grant; Half-Life; Health; Heart; Homeostasis; Hour; Human; Hyperglycemia; Hypothalamic structure; Injury; Kidney; Lead; Leptin; Light; Liver; Low-Density Lipoproteins; Maintenance; Measures; Metabolic Activation; Modeling; Molecular; Mus; Myocardial Infarction; Nature; Neuromodulator; Neurotransmitters; Norepinephrine; Nuclear; Obese Mice; Obesity; Pathway interactions; Pattern; Performance; Peripheral; Phenethylamines; Physiological; Plasma; Procedures; Process; Property; Proteins; Rattus; Relative (related person); Research; Rodent; Serotonin; Serum; Siberian Hamster; Signaling Molecule; Skeletal Muscle; Smooth Muscle; Specificity; Stomach; Stroke; TNFRSF11B gene; Therapeutic Agents; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Thyroxine; Time; Tissues; Triiodothyronine; Very low density lipoprotein; Work; apolipoprotein B-100; blood glucose regulation; catecholamine inhibitor; design; feeding; human GPRC5C protein; in vivo; induced hypothermia; interest; member; natural hypothermia; novel; obesity treatment; particle; respiratory; thyronamine

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the chemical, pharmacological, and physiological aspects of thyroid hormone action such that safer and more effective therapeutic agents can be developed that act at targets of the thyroid hormone endocrine system. We recently discovered a novel class of endogenous compounds called thyronamines that are chemical derivatives of thyroxine (T4) and may be decarboxylated and deiodinated metabolites of T4. 3-Iodothyronamine (T1AM), the most active member identified to date of this class, has no affinity for the nuclear thyroid hormone receptors TR1 and TR2; instead, T1AM is a potent agonist of an orphan GPCR called TAAR1 and is an inhibitor of catecholamine plasma membrane vesicular packaging transporters. In rodents and humans T1AM is found in circulation and tissues, and measured tissue levels are substantially higher than circulating levels, although it remains possible that the measured circulating levels are "free" and not "total" T1AM. Circulating T1AM is tightly bound to a unique serum binding protein which we have recently identified as apoB-100, the major protein component of low density lipoprotein (LDL) and very low density lipoprotein (VLDL) particles. Acute administration of T1AM rapidly induces hypothermia, bradycardia, and hyperglycemia in rodents. In addition, acute, high-dose T1AM induces a profound fueling shift away from carbohydrates and toward fat burning in Siberian hamsters, a hibernating rodent, as well as mice. This fueling change is characterized by a change in respiratory quotient (RQ) to 0.7 that persists for 48 hours after a single dose of T1AM in the hibernating rodent. T1AM has very unusual pharmacokinetic properties for a biogenic primary phenethylamine. The plasma half-life of T1AM is 5.5 hr in mice whereas half-lives of 1-2 min are the norm for chemically similar biogenic amines such as seratonin and dopamine. In addition, we have found that 2-week daily dosing of T1AM with doses approaching the 5g/kg range lead to significant weight loss in diet-induced obese mice. Results from pair-feeding studies unambiguously demonstrate that the observed chronically administered, low-dose T1AM induced reduction in body weight results from a decrease in energy intake and not an increase in energy expenditure. Thus it appears that T1AM is an endogenous anorectic agent, with a biological activity on feeding behavior similar to leptin and melanocortins, which are endogenous signaling molecules that act via central pathways in the actuate nucleus of the hypothalamus. The research proposed for the next grant period seeks to better define the biosynthetic origins of T1AM, the mechanisms by which it is transported and delivered to tissues, and the nature and mechanism behind the observed reduction in body weight. The research plan is designed around the following specific aims: (1) Identify and characterize T1AM serum binding protein(s); (2) Determine whether T1AM is derived from T4, and whether this conversion happens in the thyroid gland or in the extrathyroidal periphery; and (3) Develop chronic dosing procedures for T1AM and study the effects of chronic T1AM treatment on body weight loss in rodent obesity models.

描述（由申请人提供）：本研究的长期目标是了解甲状腺激素作用的化学、药理学和生理学方面，以便开发更安全、更有效的治疗药物，作用于甲状腺激素内分泌系统的靶点。我们最近发现了一类新的内源性化合物，称为甲状腺素胺，是甲状腺素（T4）的化学衍生物，可能是T4的脱羧和脱碘代谢产物。3-碘甲腺原氨酸（T1 AM）是迄今为止发现的该类中最活跃的成员，对核甲状腺激素受体TR 1和TR 2没有亲和力;相反，T1 AM是一种称为TAAR 1的孤儿GPCR的有效激动剂，并且是儿茶酚胺质膜囊泡包装转运蛋白的抑制剂。在啮齿动物和人类中，T1 AM存在于循环和组织中，测量的组织水平显著高于循环水平，尽管测量的循环水平仍然可能是“游离”而不是“总”T1 AM。循环T1 AM与一种独特的血清结合蛋白紧密结合，我们最近将其鉴定为apoB-100，apoB-100是低密度脂蛋白（LDL）和极低密度脂蛋白（VLDL）颗粒的主要蛋白组分。T1 AM的急性给药在啮齿动物中迅速诱导体温过低、心动过缓和高血糖症。此外，急性高剂量T1 AM诱导西伯利亚仓鼠（一种冬眠啮齿动物）以及小鼠从碳水化合物向脂肪燃烧的深刻燃料转变。这种燃料供给变化的特征在于，在冬眠啮齿动物中，在T1 AM单次给药后，呼吸商（RQ）变化为0.7，并持续48小时。T1 AM具有非常不寻常的药代动力学特性的生物原主要苯乙胺。T1 AM在小鼠中的血浆半衰期为5.5小时，而1-2分钟的半衰期是化学上类似的生物胺如血清素和多巴胺的标准值。此外，我们发现，2周每天给予T1 AM，剂量接近5g/kg范围，导致饮食诱导的肥胖小鼠体重显著减轻。配对喂养研究的结果明确表明，观察到的长期给药、低剂量T1 AM诱导的体重减轻是由于能量摄入减少，而不是能量消耗增加。因此，T1 AM似乎是一种内源性厌食剂，对进食行为具有类似于瘦素和黑皮质素的生物活性，瘦素和黑皮质素是通过下丘脑致动核中的中枢通路起作用的内源性信号传导分子。下一个资助期的研究旨在更好地定义T1 AM的生物合成起源，它被运输和递送到组织的机制，以及观察到的体重减轻背后的性质和机制。研究计划围绕以下具体目标设计：（1）鉴定和表征T1 AM血清结合蛋白;（2）确定T1 AM是否来源于T4，以及这种转化是否发生在甲状腺或甲状腺外外周;（3）开发T1 AM的长期给药程序，并研究长期T1 AM治疗对啮齿动物肥胖模型体重减轻的影响。