PHYSIOLOGY OF THYROID HORMONE-DEPENDENT GENE EXPRESSION
甲状腺激素依赖性基因表达的生理学
基本信息
- 批准号:8500239
- 负责人:
- 金额:$ 36.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AccountingAdenovirusesAdverse effectsAgingApoptosisBindingBiochemicalBiologicalBrown FatCell NucleusCell ProliferationCellsChronicCodon NucleotidesCuesDefectDevelopmentDirect Lytic FactorsElderlyEmployee StrikesEnergy MetabolismEngraftmentErinaceidaeExcisionFunctional disorderGene ExpressionGene Expression ProfilingGenesGeneticGenetic TranslationGrowth and Development functionHumanHypothalamic structureIn VitroIndiumInfectionInjuryIodide PeroxidaseIodineMediatingMessenger RNAMicroarray AnalysisMolecularMusMuscleMuscle CellsMuscle DevelopmentMuscle FibersMuscle ProteinsMuscle satellite cellMyoblastsMyopathyNatural regenerationNeonatalNuclear ReceptorsPathway interactionsPatientsPhysiologicalPhysiologyPituitary GlandPlasmaPlasma CellsPreventionProcessProductionProliferatingRegulationRestSelenocysteineSignaling ProteinSkeletal MuscleSkeletal muscle injurySkinSourceTNFRSF11B geneTamoxifenTechniquesTestingTherapeuticThyroid HormonesThyrotoxicosisThyroxineTimeTissuesTriiodothyronineWild Type Mousecell typedeiodinationhuman tissueimprovedin vivoinjuredkeratinocytemdx mousemuscle metabolismmuscle regenerationnotch proteinpituitary thyroid axisprecursor cellprohormonerepairedresponsesarcopeniasatellite cellskeletal muscle differentiationtranscription factor
项目摘要
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):甲状腺激素(TH)是几乎所有人体组织正常生长、发育和功能所必需的。本研究将探讨TH如何控制骨骼肌分化、再生和功能。骨骼肌是公认的TH靶标。TH在很大程度上通过对骨骼肌代谢的影响来控制静息能量消耗。甲状腺激素对肌肉再生影响的一个戏剧性例子发生在营养不良(mdx)小鼠身上,在这种小鼠身上,实验性甲状腺毒症加速了肌细胞的破坏,而当小鼠甲状腺功能减退时,这一过程被延缓。尽管如此,以及甲状腺功能减退和甲状腺中毒患者的肌肉功能障碍,但TH在骨骼肌中的作用机制尚不清楚。促甲状腺激素作用的第一步是原激素T4的5‘单去碘化,通过1型和2型硒化去碘酶(D1和D2)形成3,5,3’三碘甲状腺原氨酸(T3)。形成的T3占了T4的大部分作用。T3的作用需要与核受体(TR1和TR2)结合。3型脱碘酶(D3)从碘甲状腺原氨酸核中去除一个或两个内环碘,催化了T3作用的终止和T4活化的预防。激活T4的D2(但不是D1)和使T4和t3失活的D3都在相当于肌肉干细胞的卫星细胞中表达。这些去碘酶的存在允许调节细胞内卫星细胞T3浓度,以响应各种独立于循环TH水平的细胞信号。一个显著的例子发生在实验性肌肉损伤后,它诱导Notch、Wnt/2-catenin、Sonic hedgehog、Tgf2和Hif11等基因的增加,所有这些基因都被认为可以激活Dio3基因。这导致损伤区域短暂的早期D3增加,持续8-10天,并与卫星细胞和成肌前体细胞的扩增有关。FoxO3介导的D2增加是随着细胞内T4到T3转化的增加而发生的。细胞内T3的增加促进成肌细胞前体池的分化,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D2KO小鼠中,受损肌肉的修复明显延迟,并且依赖T3的MyoD1及其下游靶点保持低水平,这表明细胞内d2介导的T3生成的增加是正常再生和分化所必需的。本项目将利用遗传和生化技术评估D3和D2作用下肌肉细胞内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性操作是否可用于增强诸如创伤性或退行性肌肉损伤或老年人肌肉减少症等疾病的治疗。
项目成果
期刊论文数量(0)
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PHILIP REED LARSEN其他文献
PHILIP REED LARSEN的其他文献
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{{ truncateString('PHILIP REED LARSEN', 18)}}的其他基金
PHYSIOLOGICAL ROLE OF THYROXINE-BINDING PROTEINS
甲状腺素结合蛋白的生理作用
- 批准号:
7325756 - 财政年份:2007
- 资助金额:
$ 36.6万 - 项目类别:
PHYSIOLOGICAL ROLE OF THYROXINE-BINDING PROTEINS
甲状腺素结合蛋白的生理作用
- 批准号:
7173130 - 财政年份:2007
- 资助金额:
$ 36.6万 - 项目类别:
PHYSIOLOGICAL ROLE OF THYROXINE-BINDING PROTEINS
甲状腺素结合蛋白的生理作用
- 批准号:
7555401 - 财政年份:2007
- 资助金额:
$ 36.6万 - 项目类别:
Selenodeiodinase processing by the proteasome system
蛋白酶体系统处理硒代碘化酶
- 批准号:
6795500 - 财政年份:2003
- 资助金额:
$ 36.6万 - 项目类别:
Selenodeiodinase processing by the proteasome system
蛋白酶体系统处理硒代碘化酶
- 批准号:
6688170 - 财政年份:2003
- 资助金额:
$ 36.6万 - 项目类别:
SELENODEIODINASE PROCESSING BY THE PROTEASOME SYSTEM
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- 资助金额:
$ 36.6万 - 项目类别:
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- 批准号:
6224954 - 财政年份:2001
- 资助金额:
$ 36.6万 - 项目类别:
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- 批准号:
6628589 - 财政年份:2001
- 资助金额:
$ 36.6万 - 项目类别:
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$ 36.6万 - 项目类别:
PHYSIOLOGICAL ROLE OF THYROXINE-BINDING PROTEINS
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2807351 - 财政年份:1998
- 资助金额:
$ 36.6万 - 项目类别:
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