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: 10444923
• 负责人: GWEN V CHILDS
• 金额: $ 60.14万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10444923
• 关键词: Ablation; Adult; Aging; Anterior Pituitary Gland; Benign; Biological Assay; Cell Culture Techniques; Cell Cycle Inhibition; Cell Differentiation process; Cell Fate Control; Cell Lineage; Cell Maintenance; Cells; Clinical; Craniocerebral Trauma; Data; Development; Endocrine; Endocrine System Diseases; Epigenetic Process; Equilibrium; Exposure to; Fertility; Gender; Genetic; Genetic Transcription; Genetic Translation; Goals; Homeostasis; Hormonal; Hormonal Change; Hormones; Human; Injury; Knockout Mice; Knowledge; Lead; Leptin; Link; Malignant neoplasm of pituitary gland; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Metabolic Diseases; Mission; Molecular; Morbidity - disease rate; Natural regeneration; Organism; Overnutrition; Pathologic; Physiological; Pituitary Gland; Pituitary Hormones; Play; Polyribosomes; Population; Process; Proteins; Public Health; RNA; Recovery; Regulation; Repression; Research; Resources; Role; Signal Transduction; Somatotrope Cell; Stimulus; Testing; Therapeutic; Therapeutic Intervention; Tissues; Translations; United States National Institutes of Health; Work; adipokines; base; cancer recurrence; cancer stem cell; cancer therapy; cell type; chromatin remodeling; cofactor; cohort; gender difference; hormone deficiency; in vivo; mouse model; novel diagnostics; novel therapeutic intervention; progenitor; reproductive; response; stem; stem cell function; stem cell population; stem cell self renewal; stem cells; stem-like cell; subfertility; tissue degeneration; tissue injury; tissue regeneration; tissue repair; transcriptome sequencing; tumor; tumor progression

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.

概括 垂体前叶作为机体的内分泌核心，调节荷尔蒙的合成和 分泌以适应不断变化的代谢和生殖需求。垂体来源的缺陷 由于遗传原因、头部受伤、营养不足或过度、或垂体癌导致的激素 治疗导致严重的发病率。人们早就知道垂体前叶细胞具有 命运的显着可塑性表明干细胞样细胞群的存在。然而，无论干 细胞确实有助于细胞可塑性和垂体恢复以及控制的潜在机制 垂体细胞可塑性对垂体损伤、激素需求变化或肿瘤进展的反应 尚未成立。 mRNA 翻译控制蛋白 Musashi 已被证明发挥着关键作用 在许多组织类型中介导生理和病理干细胞功能。武藏介导干 通过抑制编码细胞周期所需蛋白质的目标 mRNA 的翻译来实现细胞自我更新 抑制和细胞分化。我们的数据表明 Musashi 在成人前部广泛表达 垂体非干细胞群以及垂体干细胞。 本申请的总体目标是评估受调控的 mRNA 翻译的总体作用，以及 武藏蛋白特别是介导垂体细胞命运的适应性变化。中心假设 武藏不仅控制垂体干细胞/祖细胞的分化，还控制可塑性 成人垂体中产生激素的细胞。具体来说，目标 1 的研究将使用体内 小鼠模型和细胞培养方法来检验武藏在过程中调节细胞可塑性的假设 组织再生以及发育性垂体干/祖细胞功能。目标 2 的研究将使用 基于多核糖体的无偏见 RNA 测序方法来检验 Musashi 具有性别特异性的假设 控制干细胞/祖细胞和干细胞中细胞命运决定的 mRNA 靶点和 RNA 靶向机制 成人激素产生细胞群的适应性反应。 这项研究的结果将充分告知该领域 Musashi 活性和 mRNA 翻译的作用 控制垂体细胞可塑性和干/祖细胞功能。此外，这些拟议的研究 涉及内分泌和代谢疾病的治疗方法，特别是由垂体引起的疾病 的不足。由于激素替代策略不能完全模仿生理脉动分泌模式， 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。这将对垂体合并症的性别适当的治疗范例产生积极影响 激素缺乏、代谢疾病和头部受伤后垂体组织修复。

项目成果

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: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
• 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