Control of pituitary cell plasticity through regulated mRNA translation

摘要 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。 分泌，以适应不断变化的新陈代谢和生殖需求。垂体源缺乏症 荷尔蒙，由于遗传原因、头部损伤、营养不足或过度营养，或由于脑垂体癌 治疗会导致严重的发病率。众所周知，垂体前叶的细胞具有 命运的显着可塑性表明存在干细胞样细胞群。然而，无论是茎 细胞确实有助于细胞的可塑性和脑下垂体的恢复，以及控制 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 没有得到证实。Mrna翻译控制蛋白Musashi已被证明起着关键作用。 在许多组织类型中调节生理和病理干细胞的功能。武藏调理茎 通过抑制编码细胞周期所需蛋白质的靶mRNAs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，武藏广泛地表达在成人的前额 在非干细胞群体中的垂体，以及在垂体干细胞中。 此应用程序的总体目标是评估一般受调控的mRNA翻译的作用，以及 武藏蛋白在调节脑下垂体细胞命运的适应性变化中具有特异性。中心假说 武藏既控制着垂体干/祖细胞的分化，也控制着它的可塑性 成年脑下垂体中产生荷尔蒙的细胞。具体地说，AIM 1的研究将在体内使用这两种方法 小鼠模型和细胞培养方法验证武藏调节细胞可塑性的假说 组织再生以及发育中的垂体干细胞/祖细胞功能。AIM 2的研究将使用 无偏多聚体、RNA测序方法检验武藏具有性别特异性的假设 在干细胞/祖细胞和成骨细胞中控制细胞命运决定的mRNA靶向和RNA靶向机制 成体激素产生细胞群体的适应性反应。 这项研究的发现将使该领域充分了解武藏活动和信使核糖核酸翻译的作用。 在控制脑垂体细胞的可塑性和干/祖细胞功能方面。此外，这些拟议的研究 与内分泌和代谢疾病的治疗方法有关，特别是由脑下垂体引起的 不足之处。由于激素替代策略不能完全模拟生理脉动分泌机制， 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 进步。这将积极影响适合性别的联合垂体治疗方案。 颅脑损伤后激素缺乏、代谢性疾病和脑下垂体组织修复。

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.