Glucocorticoid dynamics in health and disease

糖皮质激素在健康和疾病中的动态

• 批准号: MR/R010919/1
• 负责人: Stafford Lightman
• 金额: $ 235.42万
• 依托单位: University of Bristol
• 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%2FR010919%2F1
• 关键词: Glucocorticoid; dynamics; health; disease

The secretion of the stress hormone cortisol by the adrenal gland is controlled by the activity of the hypothalamus and pituitary gland. We have shown that this is a very dynamic system with both an hourly (ultradian) and a 24 hour (circadian) rhythm. This results in oscillating levels of cortisol in the blood and in all the tissues of the body.Patients who lack the hormone cortisol are treated with pills containing cortisol two or three times a day. This results in hormone levels that lack any ultradian activity. These patients often lack energy, feel generally apathetic, have high levels of unemployment and double the mortality of normal people of the same age.In this grant application we plan to investigate the mechanisms underlying the increased mortality and morbidity in these patients, by studying the importance of oscillating levels of cortisol both in an animal model and in man. In the animal model we will investigate the biological mechanisms through which pulsatility affects neural function both at the level of cellular function and animal behaviour. In human volunteers we will use brain scanning (fMRI) and changes in pupil size to look at the brain pathways responding to changes in cortisol pattern.Ultimately, we hope to better understand the brain pathways associated with apathy, and hope that this will enable us to develop more appropriate therapy not only for Addison's disease, but also other conditions associated with apathy and abnormal adrenal activity such as depression, PTSD and chronic fatigue syndrome.

肾上腺分泌的应激激素皮质醇受下丘脑和脑垂体的活动控制。我们已经表明，这是一个非常动态的系统，具有每小时（超昼夜）和24小时（昼夜）节律。这导致血液和身体所有组织中的皮质醇水平波动。缺乏激素皮质醇的患者每天服用两到三次含有皮质醇的药丸。这导致激素水平缺乏任何超日活动。这些患者通常缺乏活力，普遍感到冷漠，失业率高，死亡率是同龄正常人的两倍。在这项拨款申请中，我们计划调查这些患者死亡率和发病率增加的潜在机制，通过研究动物模型和人体中皮质醇水平振荡的重要性。在动物模型中，我们将通过以下方式研究生物学机制：该脉动性在细胞功能和动物行为水平上影响神经功能。在志愿者中，我们将使用大脑扫描（fMRI）和瞳孔大小的变化来观察大脑对皮质醇模式变化的反应。最终，我们希望更好地了解与冷漠相关的大脑通路，并希望这将使我们能够开发出更合适的治疗方法，不仅适用于阿狄森氏病，还适用于与冷漠和异常肾上腺活动相关的其他疾病，如抑郁症，创伤后应激障碍和慢性疲劳综合征。

项目成果

Time of day influences stress hormone response to ketamine.

一天中的时间影响应力激素对氯胺酮的反应。

• DOI: 10.1111/jne.13194
• 发表时间: 2022-10
• 期刊: JOURNAL OF NEUROENDOCRINOLOGY
• 影响因子: 3.2
• 作者: Birnie, Matthew T.;Eapen, Alen, V;Kershaw, Yvonne M.;Lodge, David;Collingridge, Graham L.;Conway-Campbell, Becky L.;Lightman, Stafford L.
• 通讯作者: Lightman, Stafford L.

The emerging importance of ultradian glucocorticoid rhythms within metabolic pathology.

• DOI: 10.1016/j.ando.2018.03.003
• 发表时间: 2018-06
• 期刊: Annales d'endocrinologie
• 作者: Flynn BP;Conway-Campbell BL;Lightman SL
• 通讯作者: Lightman SL

Tonic and phasic effects of reward on the pupil: implications for locus coeruleus function.

• DOI: 10.1098/rspb.2022.1545
• 发表时间: 2022-09-14
• 期刊: PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
• 影响因子: 4.7
• 作者: Cole, Laura;Lightman, Stafford;Clark, Rosie;Gilchrist, Iain D.
• 通讯作者: Gilchrist, Iain D.

Involvement of CREB-regulated transcription coactivators (CRTC) in transcriptional activation of steroidogenic acute regulatory protein (Star) by ACTH.

CREB ​​调节的转录共激活因子 (CRTC) 参与 ACTH 对类固醇生成急性调节蛋白 (Star) 的转录激活。

• DOI: 10.1016/j.mce.2019.110612
• 发表时间: 2020
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Smith LIF

Circadian regulation of hippocampal function is disrupted with corticosteroid treatment.

海马功能的昼夜节律调节被皮质类固醇治疗中断。

• DOI: 10.1073/pnas.2211996120
• 发表时间: 2023-04-11
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1