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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=667217
• 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 & corticotropes *** We shall test the hypothesis that, in the pituitary gland of adult mice that were exposed to prenatal stress: (i) the ability of GC to stimulate the release of signaling molecules from FS cells is reduced; 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：***哺乳动物应激时促肾上腺皮质激素释放激素（CRH）的释放刺激垂体促肾上腺皮质激素（ACTH）的分泌。反过来，ACTH触发肾上腺分泌糖皮质激素（GC）。GC对crh诱发的ACTH释放具有快速（非基因组）抑制作用。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，以及产前应激动物模型中gc介导的ACTH释放负反馈快速期失调的细胞适应性。我们的长期目标是了解ACTH释放受各种环境压力因素影响的机制。***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），这两种信号分子由邻近的胶质样垂体滤泡星状细胞（FS）释放；（ii）产前应激诱导的GC抑制ACTH分泌快速期的失调是由FS细胞信号分子释放减少以及促皮质细胞和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，我们将验证crh诱发的去极化被逆转的假设：(a) AnxA1通过甲酰基肽受体（FPR）降低背景TRPC电流；(b) NO，增强背景trek - 1k +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***利用POMC-eGFP小鼠垂体切片共聚焦成像，我们将验证GC受体对FS细胞的刺激导致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+信号的假设。******项目3：产前应激对FS细胞与促肾上腺皮质激素相互作用的影响***我们将验证以下假设：在暴露于产前应激的成年小鼠脑垂体中：(i) GC刺激FS细胞释放信号分子的能力降低；（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：***我们的研究结果将揭示gc介导的ACTH释放负调控快速期的细胞机制。这一知识将是我们对内分泌对压力反应的生理调节的总体理解的重大进步。