Chemical Biology Studies of 3-Iodothyronamine and Related Thyroid Hormone Metabol

描述（由申请人提供）：本研究的长期目标是了解甲状腺激素及其生物活性代谢物的化学，生化和生物学方面，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名为甲状腺胺的新型内源性化合物，它是甲状腺素（T4）的化学衍生物。3-碘甲状腺胺（T1AM）是迄今为止发现的该类中最活跃的成员，它对甲状腺激素核受体TR1和TR2没有亲和力，但具有独特的潜在治疗作用。单剂量T1AM可迅速引起啮齿动物体温过低、心动过缓和高血糖。此外，在西伯利亚仓鼠（一种冬眠的啮齿动物）和小鼠中，T1AM诱导了从碳水化合物到脂肪燃烧的深刻能量转变。我们最近证明，长期服用低剂量的T1AM可以抑制肥胖小鼠的摄食行为；也就是说，像瘦素一样，T1AM似乎是一种内源性的厌食剂。在啮齿类动物和人类中，内源性T1AM在循环和组织中的水平与T4的主要生物活性代谢物之一T3相似。与T4类似，循环中的T1AM与血清结合蛋白紧密结合，这些结合蛋白与用于运输T4的结合蛋白不同。在人血清中，T1AM与低密度脂蛋白（LDL）颗粒的主要脂蛋白载脂蛋白-100特异性结合，表明T1AM在调节胆固醇稳态中具有潜在作用。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，而化学性质相似的生物胺如血清素和多巴胺的半衰期为1-2分钟。此外，T1AM的分布体积非常大，表明T1AM从循环广泛分布到所有组织，包括脂肪和肌肉等灌注不良的组织。与此进一步一致的发现是，T1AM被稳健地转运到多种细胞类型，包括来自脂肪和骨骼肌的细胞，这种转运机制对T1AM具有高度选择性，并且通过不涉及生物胺再摄取转运体家族成员的机制发生。了解T1AM的这些不寻常的生化特性及其揭示的潜在生理学是本资助提案的直接目标。研究计划包括以下具体目标：(1)。分离小鼠和大鼠血清中T1AM结合蛋白并对其进行鉴定(2)确定T1AM是否影响体内胆固醇摄取和代谢；(3)发现并表征T1AM的共轭代谢产物；(4)确定细胞内摄取T1AM的机制，寻找T1AM靶蛋白。

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the chemical, biochemical, and biological aspects of thyroid hormone and its bioactive metabolites 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). 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, but nevertheless has unique and potentially therapeutically useful biological actions. Single doses of T1AM rapidly induce hypothermia, bradycardia, and hyperglycemia in rodents. In addition, T1AM induces a profound fueling shift away from carbohydrates and toward fat burning in Siberian hamsters, a hibernating rodent, as well as mice. We recently demonstrated that chronic administration of low doses of T1AM inhibit feeding behavior in obese mice; i.e. like leptin, T1AM appears to act as an endogenous anorectic agent. In rodents and humans endogenous T1AM is found in circulation and tissues at levels that are similar to that of T3, one of the principle bioactive metabolites of T4. Similarly to T4, circulating T1AM is tightly bound to serum binding proteins and these binding proteins are different from those used to transport T4. In human serum, T1AM binds specifically to apoB-100, the primary lipoprotein of low density lipoprotein (LDL) particles, suggesting a potential role of T1AM in modulating cholesterol homeostasis. 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 serotonin and dopamine. In addition, the volume of distribution of T1AM is very high suggesting that T1AM distributes widely from circulation into all tissues including poorly perfused tissues such as fat and muscle. Further consistent with this is the finding that T1AM is robustly transported into a variety of cell types, including cells derived from fat and skeletal muscle, and this transport is mechanism is highly selective for T1AM and occurs by a mechanism that does not involve a member of the biogenic amine reuptake transporter family. Understanding these unusual biochemical properties of T1AM and the underlying physiology they reveal is the direct goal of this grant proposal. The research plan is comprised of the following Specific Aims: (1) . Isolate and Characterize T1AM binding proteins in mouse and rat serum; (2) Determine whether T1AM affects cholesterol uptake and metabolism in vivo; (3) Discover and characterize conjugated metabolites of T1AM.; (4) Determine the mechanism of intracellular uptake of T1AM and search for T1AM target proteins.