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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684402
• 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，应激时促肾上腺皮质激素释放激素 (CRH) 的释放会刺激垂体中促肾上腺皮质激素的促肾上腺皮质激素 (ACTH) 分泌。 ACTH 反过来会触发肾上腺分泌糖皮质激素 (GC)。 GC 对 CRH 诱发的 ACTH 释放产生快速（非基因组）抑制。在暴露于产前应激的成年啮齿动物中发现了GC介导的反馈快速阶段的失调。 ******目标和假设：*** 我们的短期目标是阐明垂体 ACTH 释放快速负调节的细胞机制，以及导致 GC- 快速相失调的细胞适应。在产前应激动物模型中调节 ACTH 释放的负反馈。我们的长期目标是了解各种环境压力因素影响 ACTH 释放的机制。 *** 我们的一般假设是：(i) GC 对促肾上腺皮质激素释放 ACTH 的快速抑制作用是通过两种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)，它们是由促肾上腺皮质激素释放的邻近的神经胶质样垂体滤泡细胞（FS）； (ii) 产前应激诱导的 GC 抑制 ACTH 分泌的快速阶段失调是由 FS 细胞释放信号分子的减少以及促肾上腺皮质激素和 FS 细胞中受体/离子通道表达的变化引起的。 ******项目 1：AnxA1 和 NO 对促肾上腺皮质激素的抑制作用的细胞机制*** 通过使用 POMC-eGFC 小鼠的促肾上腺皮质激素，我们将测试以下假设：CRH 诱发的去极化被逆转：（a ) AnxA1，通过甲酰肽受体 (FPR) 发挥作用，减少背景 TRPC 电流； (b) NO，增强背景 TREK-1 K+ 电流和/或抑制 TRPC 电流。******项目 2：FS 细胞释放 AnxA1 和 NO 在 GC 快速抑制作用中的作用***使用 POMC-eGFP 小鼠垂体切片的共聚焦成像，我们将测试以下假设：刺激 FS 细胞上的 GC 受体会导致 AnxA1 和 NO 的释放，进而作用于邻近的促肾上腺皮质激素抑制 CRH 诱发的 Ca2+ 信号。 ******项目 3：产前应激对 FS 细胞之间相互作用的影响，以及 (ii) 促肾上腺皮质激素中 FPR、背景 TRPC 或 TREK-1 通道的表达发生变化。 ******意义：***我们的结果将揭示GC介导的ACTH释放负调节快速阶段的细胞机制。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。