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)的释放刺激了脑下垂体促肾上腺皮质激素(ACTH)的分泌。ACTH反过来触发肾上腺分泌糖皮质激素(GC)。GC对CRH诱导的ACTH释放有快速(非基因组)抑制作用。在暴露于产前应激的成年啮齿动物中，在GC介导的反馈的这一快速阶段发现了失调。*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，以及在产前应激动物模型中导致GC介导的ACTH释放负反馈快速阶段调节失调的细胞适应。我们的长期目标是了解各种环境应激源影响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的快速抑制作用是通过相邻的胶质样垂体腺泡状细胞(FS)释放的两个信号分子：膜联蛋白A1(AnxA1)和一氧化氮(NO)的旁分泌作用介导的；以及(Ii)产前应激导致GC抑制ACTH分泌的快相失调是由于FS细胞释放的信号分子减少以及皮质和FS细胞受体/离子通道表达的变化所致。*项目1：AnxA1和NO抑制促肾上腺皮质激素作用的细胞机制*通过使用POMC-eGFC小鼠的促肾上腺皮质激素，我们将检验这样的假设：(A)AnxA1通过甲酰肽受体(FPR)作用于减少背景TRPC电流的CRH诱发的去极化；(B)NO，增强背景Trek-1 K+电流和/或抑制TRPC电流。*项目2：AnxA1和FS细胞释放NO在GC快速抑制作用中的作用*使用POMC-EGFP小鼠脑片上的共聚焦成像，我们将检验这样一种假设，即刺激FS细胞上的GC受体导致AnxA1和NO的释放，进而作用于邻近的皮质细胞，以抑制CRH诱导的钙信号。*项目3：产前应激对FS细胞相互作用的影响以及(Ii)促肾上腺皮质激素受体、背景TRPC或Trek-1通道表达的变化。*意义：*我们的结果将揭开GC介导的ACTH释放负调控快速阶段背后的细胞机制。这一知识将是我们对内分泌应激反应的生理调节的一般理解方面的重大进步。