Thyroid Hormone Action

甲状腺激素作用

• 批准号: 8106871
• 负责人: THOMAS Sterling SCANLAN
• 金额: $ 38.5万
• 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/8106871
• 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. PUBLIC HEALTH RELEVANCE: Thyroid hormone has important actions for maintaining health in both children and adults. These actions must be in balance as both over-and under-abundance of thyroid hormone can result in serious disorders and disease. The primary form of thyroid hormone made in the thyroid gland is thyroxin, which is metabolized into other biologically active products such as iodothyronines and thyronamines. The purpose of this research is to understand the actions of thyroid hormone and its bioactive metabolites at the molecular, cellular, and tissue level such that safer and more effective therapeutic agents that target the actions of thyroid hormone can be developed.

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目标。我们最近发现了一类新的内源性化合物，称为甲状腺胺，它是甲状腺素（T4）的化学衍生物，可能是T4的脱羧和去碘代谢产物。3-碘甲状腺胺（3-Iodothyronamine, T1AM）是迄今为止鉴定出的该类中最活跃的成员，与甲状腺激素核受体TR1和TR2没有亲和力；相反，T1AM是一种名为TAAR1的孤儿GPCR的有效激动剂，是儿茶酚胺质膜囊泡包装转运蛋白的抑制剂。在啮齿类动物和人类的血液循环和组织中发现了T1AM，测量到的组织水平大大高于循环水平，尽管仍然有可能测量到的循环水平是“游离”而不是“总”T1AM。循环T1AM与一种独特的血清结合蛋白紧密结合，我们最近鉴定为apoB-100，它是低密度脂蛋白（LDL）和极低密度脂蛋白（VLDL）颗粒的主要蛋白质成分。急性给药T1AM可迅速引起啮齿动物体温过低、心动过缓和高血糖。此外，急性、高剂量的T1AM会导致西伯利亚仓鼠（一种冬眠的啮齿动物）和老鼠的能量从碳水化合物向脂肪燃烧转变。这种燃料变化的特征是呼吸商（RQ）变化到0.7，在冬眠的啮齿动物中，单剂量T1AM后持续48小时。T1AM作为一种生物原苯乙胺具有非常不寻常的药代动力学特性。T1AM在小鼠体内的血浆半衰期为5.5小时，而化学上类似的生物胺如血清素和多巴胺的半衰期为1-2分钟。此外，我们还发现，每天给药2周，剂量接近5g/kg范围的T1AM可以显著减轻饮食诱导的肥胖小鼠的体重。配对喂养研究的结果明确表明，观察到的长期低剂量T1AM诱导的体重减轻是由于能量摄入的减少，而不是能量消耗的增加。因此，T1AM似乎是一种内源性厌食剂，其对摄食行为的生物活性与瘦素和黑素皮质素相似，后者是内源性信号分子，通过下丘脑驱动核的中枢通路起作用。为下一个拨款期提出的研究旨在更好地定义T1AM的生物合成起源，其运输和传递到组织的机制，以及观察到的体重减轻背后的性质和机制。本研究计划围绕以下具体目标进行设计：(1)鉴定和表征T1AM血清结合蛋白；(2)确定T1AM是否来源于T4，这种转化是发生在甲状腺还是发生在甲状腺外周；(3)制定T1AM的慢性给药程序，研究慢性T1AM治疗对啮齿动物肥胖模型体重减轻的影响。