Regulation of adrenocorticotropic hormone secretion from the anterior pituitary gland

垂体前叶促肾上腺皮质激素分泌的调节

• 批准号: RGPIN-2018-04676
• 负责人: Tse, Amy
• 金额: $ 2.33万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=713175
• 关键词: Regulation; adrenocorticotropic; hormone; secretion; anterior

Background: In mammals, the release of corticotropin-releasing hormone (CRH) upon stress stimulates adrenocorticotropic hormone (ACTH) secretion from corticotropes in the pituitary gland. ACTH, in turn, triggers glucocorticoids (GC) secretion from the adrenal gland. GC exerts a rapid (non-genomic) suppression on the CRH-evoked ACTH release. Dysregulation in this rapid phase of GC-mediated feedback was found in adult rodents that were exposed to prenatal stress. Goals and hypotheses: Our short-term goals are to elucidate the cellular mechanisms underlying the rapid negative regulation of pituitary ACTH release, and the cellular adaptations that contribute to the dysregulation of the rapid phase of GC-mediated negative feedback of ACTH release in an animal model of prenatal stress. Our long-term goal is to understand the mechanisms by which ACTH release can be shaped by various types of environmental stressors. Our general hypotheses are: (i) the rapid inhibitory action of GC on ACTH release from corticotropes is mediated via the paracrine actions of two signaling molecules: annexin A1 (AnxA1) and nitric oxide (NO), which are released by the neighboring glial-like pituitary folliculostellate (FS) cells; and (ii) the prenatal stress-induced dysregulation of the rapid phase of GC suppression of ACTH secretion is caused by a decrease in the release of signaling molecules from FS cells and changes in the expression of receptors/ion channels in corticotropes and FS cells. PROJECT 1: Cellular mechanisms underlying the inhibitory actions of AnxA1 and NO on corticotropes By employing corticotropes from POMC-eGFC mice, we shall test the hypothesis that the CRH-evoked depolarization is reversed by: (a) AnxA1, which acts via the formyl peptide receptors (FPR) to reduce a background TRPC current; (b) NO, which enhances the background TREK-1 K+ current and/or suppresses a TRPC current. PROJECT 2: Role of AnxA1 and NO release from FS cells in the rapid inhibitory actions of GC Using confocal imaging on pituitary slices of POMC-eGFP mice, we shall test the hypothesis that the stimulation of GC receptors on FS cells causes the release of AnxA1 and NO which, in turn, acts on neighboring corticotropes to suppress the CRH-evoked Ca2+ signal. PROJECT 3: Impact of prenatal stress on the interactions between FS cells and (ii) there are changes in the expression of FPR, background TRPC or TREK-1 channels in corticotropes. Significance: Our results will unravel the cellular mechanisms underlying the rapid phase of the GC-mediated negative regulation of ACTH release. This knowledge will be a major advance in our general understanding of the physiological regulation of the endocrine response to stress.

背景： 在哺乳动物中，应激时释放皮质激素释放激素（CRH）会刺激垂体中皮质性的肾上腺皮质激素（ACTH）分泌。 ACTH反过来触发肾上腺的糖皮质激素（GC）分泌。 GC对CRH诱发的ACTH释放施加了快速（非基因组）抑制。在暴露于产前应激的成年啮齿动物中，发现GC介导的反馈的快速阶段失调。 目标和假设： 我们的短期目标是阐明垂体ACTH释放快速负调控的细胞机制，以及在产前应力动物模型中GC介导的ACTH释放的快速反馈反馈的快速调节的细胞适应性。我们的长期目标是了解各种环境压力源可以塑造ACTH释放的机制。 我们的总体假设是：（i）GC对ACTH从皮质激素释放的快速抑制作用是通过两个信号分子的旁分泌作用介导的：膜联蛋白A1（Anxa1）和一氧化氮（NO），这些氧化物（NO）是由相邻的Glial-Glial-Glial-like-like垂体的垂体folliculostartary folliculostellate（FS）细胞释放的。 （ii）ACTH分泌的GC抑制快速期的产前应力诱导的失调是由FS细胞中信号分子释放的释放以及皮质机体和FS细胞中受体/离子通道表达的变化引起的。 项目1：Anxa1抑制作用和对皮质动物的抑制作用的基础机制 通过采用来自POMC-EGFC小鼠的皮质机体，我们应检验以下假设：CRH诱发的去极化被逆转：（a）Anxa1，该anxa1通过甲基肽受体（FPR）起作用，以减少背景TRPC电流； （b）否，它可以增强背景trek-1 k+电流和/或抑制trpc电流。 项目2：Anxa1的作用和FS细胞在GC的快速抑制作用中没有释放的作用 使用共聚焦成像在POMC-EGFP小鼠的垂体切片上，我们将检验以下假设：FS细胞上GC受体的刺激会导致Anxa1的释放，而没有，而无需促进邻近的皮质激发，以抑制CRH诱发的CA2+信号。 项目3：产前应力对FS细胞与（ii）之间相互作用的影响，在皮质激发中FPR，背景TRPC或TREK-1通道的表达发生了变化。 意义： 我们的结果将揭示GC介导的ACTH释放负面调控的快速相位的细胞机制。这些知识将是我们对内分泌对压力反应的生理调节的一般理解的重大进步。