STRESS recovery

压力恢复

• 批准号: MR/V012290/1
• 负责人: Mike Shipston
• 金额: $ 72.75万
• 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: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV012290%2F1
• 关键词: STRESS; recovery

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. Many people are able to cope with chronic stress, whilst others are more susceptible, possibly because of their genetic background or other life experiences. Why some are more affected by long-term stress are unclear and this project will address this question and possibly identify strategies and drugs that may allow these people to become more resilient. When we are stressed the body releases powerful glucocorticoid hormones from an organ just above the kidneys, the adrenal gland, into the blood stream and these control many aspects of body function that are important for responding to stress. This release of glucocorticoids is intricately controlled by the brain, which regulates the electrical activity of corticotrophs, cells that are located in the pea-sized anterior pituitary gland, at the base of the brain. Stimulation of corticotroph cells by hormones released from the brain during stress results in release of the stress hormone ACTH that is released 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 over excited and release more ACTH resulting in elevated glucocorticoid levels. It had been largely assumed that once the period of chronic stress was over the behaviour of the corticotrophs simply returned to the normal "pre-stress" level.However, our remarkable recent findings reveal that corticotrophs undergo a persistent change in both their properties as well as the portfolio of genes they express. These persistent changes last for weeks after the stress is over suggesting that that the behaviour of the cells is altered and that stress regulation through their interaction with the brain and adrenal glands may then be different. This may help explain the variable ways people respond to new stressful situations after a period of chronic stress and the reason why some are resilient, while others susceptible, to the development of stress-related disorders. An important technical development means that for the first time we are now able to measure how corticotrophs behave in real-time in the living animal. We will combine this with powerful techniques that allow us to measure corticotroph activity and make predictions about how corticotrophs and their hormone output are regulated, so that we can understand how this may be modified by chronic stress. 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下，这可能会导致重大的健康问题，包括肥胖，糖尿病，心脏问题和无法集中注意力，学习新技能或科普日常生活。许多人能够科普慢性压力，而其他人则更容易受到影响，可能是因为他们的遗传背景或其他生活经历。为什么有些人更容易受到长期压力的影响尚不清楚，这个项目将解决这个问题，并可能确定可能使这些人变得更有弹性的策略和药物。当我们受到压力时，身体会从肾脏上方的器官肾上腺释放出强大的糖皮质激素进入血液，这些激素控制着身体功能的许多方面，这些方面对于应对压力非常重要。这种糖皮质激素的释放是由大脑复杂控制的，大脑调节着促肾上腺皮质激素细胞的电活动，促肾上腺皮质激素细胞位于豌豆大小的脑垂体前叶，位于大脑的底部。在应激期间，促肾上腺皮质激素细胞被从大脑释放的激素刺激，导致应激激素ACTH的释放，该应激激素ACTH被释放到血液中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。人们普遍认为，一旦慢性应激期结束，促肾上腺皮质激素细胞的行为就会简单地恢复到正常的“应激前”水平，然而，我们最近的研究结果表明，促肾上腺皮质激素细胞的性质和表达的基因组合都会发生持续变化。这些持续的变化会在压力结束后持续数周，这表明细胞的行为发生了变化，并且通过与大脑和肾上腺的相互作用进行的压力调节可能会有所不同。这可能有助于解释人们在经历一段时间的慢性压力后对新的压力情况做出反应的不同方式，以及为什么有些人有弹性，而另一些人则容易受到压力相关疾病的影响。一项重要的技术发展意味着，我们现在第一次能够在活体动物中实时测量促肾上腺皮质激素的行为。我们将联合收割机与强大的技术相结合，使我们能够测量促肾上腺皮质激素细胞的活性，并预测促肾上腺皮质激素细胞及其激素分泌是如何调节的，这样我们就可以了解慢性应激如何改变这种调节。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

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

Glucocorticoid action in the anterior pituitary gland: Insights from corticotroph physiology.

• DOI: 10.1016/j.coemr.2022.100358
• 发表时间: 2022-08
• 期刊: Current opinion in endocrine and metabolic research

LKB1 is the gatekeeper of carotid body chemosensing and the hypoxic ventilatory response.

• DOI: 10.1038/s42003-022-03583-7
• 发表时间: 2022-06-29
• 期刊: Communications biology
• 影响因子: 5.9

Corticotroph isolation from Pomc-eGFP mice reveals sustained transcriptional dysregulation characterising a mouse model of glucocorticoid-induced suppression of the hypothalamus-pituitary-adrenal axis.

• DOI: 10.1111/jne.13165
• 发表时间: 2022-07
• 期刊: JOURNAL OF NEUROENDOCRINOLOGY
• 影响因子: 3.2
• 作者: Duncan, Peter J.;McClafferty, Heather;Nolan, Oscar;Ding, Qinghui;Homer, Natalie Z. M.;Le Tissier, Paul;Walker, Brian R.;Shipston, Michael J.;Romano, Nicola;Chambers, Thomas J. G.
• 通讯作者: Chambers, Thomas J. G.

A New Perspective on Regulation of Pituitary Plasticity: The Network of SOX2-Positive Cells May Coordinate Responses to Challenge.

• DOI: 10.1210/endocr/bqac089
• 发表时间: 2022-08-01
• 期刊: Endocrinology
• 影响因子: 4.8