Control of pituitary cell plasticity through regulated mRNA translation
通过调节 mRNA 翻译控制垂体细胞可塑性
基本信息
- 批准号:10444923
- 负责人:
- 金额:$ 60.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAdultAgingAnterior Pituitary GlandBenignBiological AssayCell Culture TechniquesCell Cycle InhibitionCell Differentiation processCell Fate ControlCell LineageCell MaintenanceCellsClinicalCraniocerebral TraumaDataDevelopmentEndocrineEndocrine System DiseasesEpigenetic ProcessEquilibriumExposure toFertilityGenderGeneticGenetic TranscriptionGenetic TranslationGoalsHomeostasisHormonalHormonal ChangeHormonesHumanInjuryKnockout MiceKnowledgeLeadLeptinLinkMalignant neoplasm of pituitary glandMediatingMediator of activation proteinMessenger RNAMetabolicMetabolic DiseasesMissionMolecularMorbidity - disease rateNatural regenerationOrganismOvernutritionPathologicPhysiologicalPituitary GlandPituitary HormonesPlayPolyribosomesPopulationProcessProteinsPublic HealthRNARecoveryRegulationRepressionResearchResourcesRoleSignal TransductionSomatotrope CellStimulusTestingTherapeuticTherapeutic InterventionTissuesTranslationsUnited States National Institutes of HealthWorkadipokinesbasecancer recurrencecancer stem cellcancer therapycell typechromatin remodelingcofactorcohortgender differencehormone deficiencyin vivomouse modelnovel diagnosticsnovel therapeutic interventionprogenitorreproductiveresponsestemstem cell functionstem cell populationstem cell self renewalstem cellsstem-like cellsubfertilitytissue degenerationtissue injurytissue regenerationtissue repairtranscriptome sequencingtumortumor progression
项目摘要
SUMMARY
The anterior pituitary functions as the endocrine core of the organism, regulating hormonal synthesis and
secretion to effect adaption to changing metabolic and reproductive needs. Deficiencies of pituitary-derived
hormones, due to genetic causes, head injury, under or over-nutrition, or as a consequence of pituitary cancer
treatment cause severe morbidity. The cells of the anterior pituitary have been long known to possess
remarkable plasticity of fate suggesting the presence of stem cell-like cell populations. However, whether stem
cells do indeed contribute to cell plasticity and pituitary recovery and the underlying mechanisms that control
pituitary cell plasticity in response to pituitary injury, changing hormonal demands or tumor progression have
not been established. The mRNA translation control protein, Musashi, has been shown to plays a critical role
in mediating physiological and pathological stem cell function in many tissue types. Musashi mediates stem
cell self renewal by repressing translation of target mRNAs that encode proteins required for cell cycle
inhibition and cell differentiation. Our data indicate that Musashi is broadly expressed in the adult anterior
pituitary in non-stem cell populations, as well as in pituitary stem cells.
The overall objective of this application is to assess the role of regulated mRNA translation in general, and the
Musashi protein specifically, in mediating adaptive changes of cell fate in the pituitary. The central hypothesis
is that Musashi controls both pituitary stem/progenitor cell differentiation and also plasticity
of hormone producing cells in the adult pituitary. Specifically, studies for Aim 1 will use both in vivo
mouse models and cell culture approaches to test the hypothesis that Musashi regulates cell plasticity during
tissue regeneration as well as developmental pituitary stem/progenitor cell function. Studies for Aim 2 will use
unbiased polysome-based, RNA-sequencing approaches to test the hypothesis that Musashi has gender-specific
mRNA targets and RNA-targeting mechanisms that control cell fate decisions in stem/progenitor cells and in
adaptive responses of adult hormone-producing cell populations.
The findings from this study will fully inform the field about the role of Musashi activity and mRNA translation
in the control of pituitary cell plasticity and stem/progenitor cell function. Furthermore, these proposed studies
relate to therapeutic approaches for endocrine and metabolic diseases, specifically caused by pituitary
deficiencies. As hormone replacement strategies do not fully mimic physiological pulsatile secretion regimes,
studies that promote regeneration of missing endocrine cell lineages would be a significant clinical
improvement. This will positively impact gender-appropriate treatment paradigms for combined pituitary
hormone deficiency, metabolic disease and pituitary tissue repair after head injury.
总结
垂体前叶作为生物体的内分泌核心,调节激素合成,
分泌以适应不断变化的代谢和生殖需求。垂体源性
激素,由于遗传原因,头部受伤,营养不足或营养过剩,或由于垂体癌
治疗导致严重的发病率。很久以前就知道脑垂体前叶的细胞
命运的显著可塑性表明存在干细胞样细胞群。然而,无论是干
细胞确实有助于细胞的可塑性和垂体的恢复,以及控制垂体功能的潜在机制。
垂体细胞对垂体损伤、激素需求变化或肿瘤进展的可塑性反应,
尚未建立。mRNA翻译控制蛋白Musashi已被证明在转录过程中起着关键作用。
在许多组织类型中介导生理和病理干细胞功能。武藏介干
通过抑制编码细胞周期所需蛋白质的靶mRNA的翻译实现细胞自我更新
抑制和细胞分化。我们的数据表明,武藏广泛表达于成人前额叶,
在非干细胞群体中的垂体,以及在垂体干细胞中。
本申请的总体目标是评估一般而言受调节的mRNA翻译的作用,以及mRNA翻译的调节。
具体而言,Musashi蛋白介导垂体细胞命运的适应性变化。核心假设
武藏控制着垂体干/祖细胞的分化和可塑性
成年人脑垂体中的激素分泌细胞。具体而言,目标1的研究将在体内使用
小鼠模型和细胞培养方法来测试武藏调节细胞可塑性的假设,
组织再生以及发育垂体干/祖细胞功能。目标2的研究将使用
无偏见的基于多聚体的RNA测序方法来测试武藏具有性别特异性的假设,
mRNA靶点和RNA靶向机制,控制干/祖细胞中的细胞命运决定,
成体细胞群的适应性反应。
这项研究的结果将充分告知该领域关于武藏活动和mRNA翻译的作用
垂体细胞可塑性和干/祖细胞功能的控制。此外,这些研究建议
涉及内分泌和代谢疾病的治疗方法,特别是由垂体
缺陷由于激素替代策略不能完全模拟生理脉冲分泌机制,
促进缺失的内分泌细胞谱系再生的研究将是一项重要的临床研究,
改进.这将积极影响性别适当的治疗模式,联合垂体
激素缺乏、代谢性疾病与脑损伤后垂体组织修复
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Single and double modified salinomycin analogs target stem-like cells in 2D and 3D breast cancer models.
- DOI:10.1016/j.biopha.2021.111815
- 发表时间:2021-09
- 期刊:
- 影响因子:0
- 作者:Urbaniak A;Reed MR;Fil D;Moorjani A;Heflin S;Antoszczak M;Sulik M;Huczyński A;Kupsik M;Eoff RL;MacNicol MC;Chambers TC;MacNicol AM
- 通讯作者:MacNicol AM
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{{ truncateString('GWEN V CHILDS', 18)}}的其他基金
Control of pituitary cell plasticity through regulated mRNA translation
通过调节 mRNA 翻译控制垂体细胞可塑性
- 批准号:
10202675 - 财政年份:2018
- 资助金额:
$ 60.14万 - 项目类别:
Tropic Roles for Leptin in the Maturation of Somatotropes
瘦素在生长激素成熟中的热带作用
- 批准号:
9331911 - 财政年份:2017
- 资助金额:
$ 60.14万 - 项目类别:
Tropic Roles for Leptin in the Maturation of Somatotropes
瘦素在生长激素成熟中的热带作用
- 批准号:
9912144 - 财政年份:2017
- 资助金额:
$ 60.14万 - 项目类别:
Post-transcriptional Pathways that Signal Leptin Regulation of Gonadotropes
瘦素对促性腺激素调节的转录后信号通路
- 批准号:
9902541 - 财政年份:2016
- 资助金额:
$ 60.14万 - 项目类别:
Post-transcriptional Pathways that Signal Leptin Regulation of Gonadotropes
瘦素对促性腺激素调节的转录后信号通路
- 批准号:
9195823 - 财政年份:2016
- 资助金额:
$ 60.14万 - 项目类别:
Leptin Molecular Regulatory Mechanisms That Prevent Growth hormone Deficiency
预防生长激素缺乏的瘦素分子调节机制
- 批准号:
8968138 - 财政年份:2015
- 资助金额:
$ 60.14万 - 项目类别:
The Significance of Leptin Signals to Neonatal Somatotropes and Gonadotropes
瘦素信号对新生儿生长激素和促性腺激素的意义
- 批准号:
8294398 - 财政年份:2009
- 资助金额:
$ 60.14万 - 项目类别:
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