PHYSIOLOGY OF THYROID HORMONE-DEPENDENT GENE EXPRESSION

甲状腺激素依赖性基因表达的生理学

• 批准号: 8731196
• 负责人: PHILIP REED LARSEN
• 金额: $ 37.79万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731196
• 关键词: Accounting; Adenoviruses; Adverse effects; Aging; Apoptosis; Binding; Biochemical; Biological; Brown Fat; Cell Nucleus; Cell Proliferation; Cells; Chronic; Codon Nucleotides; Cues; Defect; Development; Direct Lytic Factors; Elderly; Employee Strikes; Energy Metabolism; Engraftment; Erinaceidae; Excision; Functional disorder; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Translation; Growth and Development function; Human; Hypothalamic structure; In Vitro; Indium; Infection; Injury; Iodide Peroxidase; Iodine; Mediating; Messenger RNA; Microarray Analysis; Molecular; Mus; Muscle; Muscle Cells; Muscle Development; Muscle Fibers; Muscle Proteins; Muscle satellite cell; Myoblasts; Myopathy; Natural regeneration; Neonatal; Nuclear Receptors; Pathway interactions; Patients; Physiological; Physiology; Pituitary Gland; Plasma; Plasma Cells; Prevention; Process; Production; Proliferating; Regulation; Rest; Selenocysteine; Signaling Protein; Skeletal Muscle; Skeletal muscle injury; Skin; Source; TNFRSF11B gene; Tamoxifen; Techniques; Testing; Therapeutic; Thyroid Hormones; Thyrotoxicosis; Thyroxine; Time; Tissues; Triiodothyronine; Wild Type Mouse; cell type; deiodination; human tissue; improved; in vivo; injured; keratinocyte; mdx mouse; muscle metabolism; muscle regeneration; notch protein; pituitary thyroid axis; precursor cell; prohormone; repaired; response; sarcopenia; satellite cell; skeletal muscle differentiation; transcription factor

DESCRIPTION (provided by applicant): Thyroid hormone (TH) is required for normal growth, development and function of nearly all human tissues. This proposal will examine how TH controls skeletal muscle differentiation, regeneration and function. Skeletal muscle is a well-recognized TH target. TH controls resting energy expenditure in large part through its effects on skeletal muscle metabolism. A dramatic example of the effect of TH on muscle regeneration occurs in the dystrophic (mdx) mouse in which experimental thyrotoxicosis accelerates myocyte destruction, while this process is retarded when mice are made hypothyroid. Despite this and the muscle dysfunction in hypothyroid and thyrotoxic patients, the mechanism(s) for the actions of TH in skeletal muscle are poorly understood. The first step in TH action is the 5' monodeiodination of the prohormone T4, to form 3,5,3' triiodothyronine (T3) by the types 1 and 2 selenodeiodinases (D1 and D2). The T3 formed accounts for most of the actions of T4. The effects of T3 require its binding to nuclear receptors (TR1 and TR2). Termination of the effects of T3 and prevention of T4 activation is catalyzed by removal of one or both inner ring iodines from the iodothyronine nucleus by the type 3 deiodinase (D3). Both the T4-activating D2 (but not D1) and the T4- and T3-inactivating D3 are expressed in the satellite cells which are the muscle stem cell equivalent. The presence of these deiodinases allows regulation of the intracellular satellite cell T3 concentration in response to various cellular cues independent of the circulating TH levels. A striking example occurs after experimental muscle injury which induces an increases in Notch, Wnt/2-catenin, Sonic hedgehog, Tgf2, and Hif11, among others, all of which are known to activate the Dio3 gene. This leads to a transient early increase of D3 in the injured region lasting 8-10 days and is associated with the expansion of the satellite and myoblast precursor cells. A FoxO3- mediated increase in D2 follows increasing intracellular T4 to T3 conversion. The increase in intracellular T3 facilitates differentiation of the myoblast precursor pool replacing the damaged myocytes. Circulating thyroid hormone concentrations remain constant throughout. In a Dio2 null (D2KO) mouse, which maintains a normal circulating T3 concentration, the repair of injured muscle is markedly delayed and the T3-dependent MyoD1 and its downstream targets remain low, indicating an increase in intracellular D2-mediated T3 production is required for normal regeneration and differentiation. This project will evaluate the effects of the dynamic changes in intracellular T3 in muscle produced by the actions of D3 and D2 using genetic and biochemical techniques. We will explore how these changes facilitate skeletal muscle differentiation and regeneration. We will also determine whether therapeutic manipulations of deiodinase activities could be used to enhance the treatment of conditions such as traumatic or degenerative muscle injury or the sarcopenia of the elderly.

描述（由申请人提供）：几乎所有人体组织的正常生长、发育和功能都需要甲状腺激素（TH）。该提案将研究 TH 如何控制骨骼肌分化、再生和功能。骨骼肌是公认的 TH 目标。 TH 在很大程度上通过其对骨骼肌代谢的影响来控制静息能量消耗。 TH 对肌肉再生影响的一个引人注目的例子发生在营养不良 (mdx) 小鼠中，其中实验性甲状腺毒症加速了心肌细胞的破坏，而当小鼠甲状腺功能减退时，这一过程会受到阻碍。尽管存在这种情况以及甲状腺功能减退和甲状腺毒症患者的肌肉功能障碍，但 TH 在骨骼肌中的作用机制仍知之甚少。 TH 作用的第一步是激素原 T4 的 5' 单脱碘作用，通过 1 型和 2 型硒代碘化酶（D1 和 D2）形成 3,5,3' 三碘甲状腺原氨酸 (T3)。形成的T3 负责T4 的大部分动作。 T3 的作用需要其与核受体（TR1 和 TR2）结合。 3 型脱碘酶 (D3) 从碘甲腺原氨酸核中去除一个或两个内环碘，从而终止 T3 的作用并防止 T4 活化。 T4 激活的 D2（但不是 D1）以及 T4 和 T3 失活的 D3 均在相当于肌肉干细胞的卫星细胞中表达。这些脱碘酶的存在可以调节细胞内卫星细胞 T3 浓度，以响应各种细胞信号，而与循环 TH 水平无关。一个引人注目的例子发生在实验性肌肉损伤后，该损伤会诱导 Notch、Wnt/2-catenin、Sonic hedgehog、Tgf2 和 Hif11 等的增加，所有这些都已知会激活 Dio3 基因。这会导致受伤区域 D3 短暂性早期增加，持续 8-10 天，并且与卫星细胞和成肌细胞前体细胞的扩张有关。 FoxO3 介导的 D2 增加伴随着细胞内 T4 到 T3 转化的增加。细胞内 T3 的增加促进成肌细胞前体库的分化，取代受损的肌细胞。循环甲状腺激素浓度始终保持恒定。在维持正常循环 T3 浓度的 Dio2 null (D2KO) 小鼠中，受损肌肉的修复明显延迟，T3 依赖性 MyoD1 及其下游靶标仍然较低，表明正常再生和分化需要增加细胞内 D2 介导的 T3 产生。该项目将利用遗传和生化技术评估 D3 和 D2 作用所产生的肌肉细胞内 T3 动态变化的影响。我们将探讨这些变化如何促进骨骼肌分化和再生。我们还将确定脱碘酶活性的治疗操作是否可用于增强对创伤性或退行性肌肉损伤或老年人肌少症等疾病的治疗。