Remodelling of corticotroph excitability in chronic stress: an integrated physiological and modelling analysis

慢性应激中促肾上腺皮质激素兴奋性的重塑：综合生理和建模分析

• 批准号: MR/R010668/1
• 负责人: Mike Shipston
• 金额: $ 54.77万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR010668%2F1
• 关键词: Remodelling; corticotroph; excitability; chronic; stress

We all experience stress whether it is because we are taking an exam or experience a frightening situation. In fact, a little bit of stress is good for us and allows us to cope with the demands of modern life. However, if we are chronically stressed this can lead to major health problems including obesity, diabetes, heart problems and inability to concentrate, learn new skills or cope with everyday life.When we are stressed the body releases powerful glucocorticoid hormones into the blood stream that control many aspects of body function. This release of glucocorticoids is intricately regulated by the control of the electrical activity of corticotroph cells, located in the pea-sized anterior pituitary gland, at the base of the brain. The electrical activity of corticotrophs is stimulated by hormones released from the brain during stress, resulting in increased release of the stress hormone ACTH into the blood to control glucocorticoid synthesis and release from the adrenal gland. Normally, the glucocorticoids themselves act to switch off the electrical activity of the corticotroph cell to prevent ACTH release and thus ultimately reducing levels of glucocorticoid released into the body. However, when we are chronically stressed the corticotroph cells become overexcited and release more ACTH resulting in elevated glucocorticoid levels. Furthemore, the glucocorticoids no longer efficiently switch off the activity of the corticotrophs.We have recently determined that in chronic stress the expression of many different proteins (ion pores) that control the electrical excitability of corticotrophs are up or down regulated. Using a mathematical model, we can make predictions of how this excitability may be changed and thus allow us to define new therapeutic targets to limit the effects of chronic stress. In this project we will exploit our mathematical model and combine this with experimental analysis of corticotroph electrical excitability and ACTH release in mice and in isolated cells. Taken together we will unravel the mechanisms by which chronic stress controls anterior pituitary corticotroph function and define mechanisms and targets for potential therapeutic strategies to limit the deleterious effects of chronic stress.

我们都经历过压力，无论是因为我们正在参加考试还是经历了可怕的情况。事实上，一点点压力对我们有好处，可以让我们科普现代生活的要求。然而，如果我们长期处于压力之下，这会导致严重的健康问题，包括肥胖、糖尿病、心脏问题以及无法集中注意力、学习新技能或科普日常生活。当我们处于压力之下时，身体会释放强大的糖皮质激素到血液中，控制身体功能的许多方面。这种糖皮质激素的释放是由位于豌豆大小的脑垂体前叶中的促肾上腺皮质激素细胞的电活动控制的复杂调节。促肾上腺皮质激素细胞的电活动受到应激期间从大脑释放的激素的刺激，导致应激激素ACTH向血液中的释放增加，以控制糖皮质激素的合成和从肾上腺的释放。正常情况下，糖皮质激素本身的作用是关闭促肾上腺皮质激素细胞的电活动，以防止ACTH释放，从而最终降低释放到体内的糖皮质激素水平。然而，当我们长期受到压力时，促肾上腺皮质激素细胞变得过度兴奋并释放更多的ACTH，导致糖皮质激素水平升高。此外，糖皮质激素不再有效地关闭活动的促肾上腺皮质激素。我们最近已经确定，在慢性应激的许多不同的蛋白质（离子孔），控制电兴奋性的促肾上腺皮质激素的表达上调或下调。使用数学模型，我们可以预测这种兴奋性如何改变，从而使我们能够定义新的治疗目标，以限制慢性压力的影响。在这个项目中，我们将利用我们的数学模型，并结合联合收割机这与实验分析促肾上腺皮质激素的电兴奋性和ACTH释放在小鼠和分离的细胞。总之，我们将解开慢性应激控制垂体前叶促肾上腺皮质激素功能的机制，并确定潜在的治疗策略，以限制慢性应激的有害影响的机制和目标。

项目成果

Chronic stress facilitates bursting electrical activity in pituitary corticotrophs

• DOI: 10.1113/jp282367
• 发表时间: 2021-12-23
• 期刊: JOURNAL OF PHYSIOLOGY-LONDON
• 影响因子: 5.5
• 作者: Duncan, Peter J.;Fazli, Mehran;Shipston, Michael J.
• 通讯作者: Shipston, Michael J.

Control of anterior pituitary cell excitability by calcium-activated potassium channels.

通过钙激活钾通道控制垂体前叶细胞的兴奋性。

• DOI: 10.1016/j.mce.2017.06.003
• 发表时间: 2018
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Shipston MJ

Protein Lipidation - Methods and Protocols

蛋白质脂化 - 方法和方案

• DOI: 10.1007/978-1-4939-9532-5_12
• 发表时间: 2019
• 作者: McClafferty H

Regulatory effects of protein S-acylation on insulin secretion and insulin action.

• DOI: 10.1098/rsob.210017
• 发表时间: 2021-03
• 期刊: Open biology
• 影响因子: 5.8
• 作者: Chamberlain LH;Shipston MJ;Gould GW
• 通讯作者: Gould GW