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）的释放刺激脑垂体中促肾上腺皮质激素（ACTH）从促肾上腺皮质激素分泌。反过来，促肾上腺皮质激素又会触发肾上腺分泌糖皮质激素（GC）。GC对CRH诱发的ACTH释放施加快速（非基因组）抑制。在这个快速阶段的GC介导的反馈失调被发现在成年啮齿动物暴露于产前压力。** 目标和假设：* 我们的短期目标是阐明垂体ACTH释放的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失调的细胞适应。我们的长期目标是了解ACTH释放的机制可以通过各种类型的环境压力来塑造。*** 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（AnxA 1）和一氧化氮（NO），它们由邻近的胶质样垂体滤泡星状（FS）细胞释放;及（ii）产前压力-促肾上腺皮质激素分泌的GC抑制的快速期的诱导失调是由FS细胞释放信号分子的减少和受体/受体表达的变化引起的。离子通道在促皮质细胞和FS细胞。** 项目1：AnxA 1和NO对促肾上腺皮质激素抑制作用的细胞机制 * 通过使用来自POMC-eGFC小鼠的促肾上腺皮质激素，我们将测试CRH诱发的去极化被以下逆转的假设：（a）AnxA 1，其通过甲酰肽受体（FPR）起作用以减少背景TRPC电流;（B）NO，其增强背景TREK-1 K+电流和/或抑制TRPC电流。项目2：FS细胞释放的AnxA 1和NO在GC快速抑制作用中的作用 * 使用POMC-eGFP小鼠的垂体切片上的共聚焦成像，我们将测试的假设，即FS细胞上的GC受体的刺激导致释放的AnxA 1和NO，这反过来又作用于相邻的促肾上腺皮质激素抑制CRH诱发的Ca 2+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）促肾上腺皮质激素细胞中FPR、背景TRPC或TREK-1通道的表达发生变化。 ****** 重要性：*** 我们的研究结果将揭开的细胞机制的快速阶段的GC介导的负调控ACTH释放。这一知识将是我们对应激内分泌反应生理调节的一般理解的一个重大进展。