Bilateral BBSRC-FAPESP: Behavioural and neuroendocrine mechanisms regulating hydromineral homeostasis - a lifelong perspective

双边 BBSRC-FAPESP：调节水矿物质稳态的行为和神经内分泌机制 - 终生视角

• 批准号: BB/J015415/1
• 负责人: David Murphy
• 金额: $ 84.03万
• 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: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ015415%2F1
• 关键词: Bilateral; BBSRC; FAPESP; Behavioural; neuroendocrine

The bodily fluids of the mammalian organism are in a constant state of flux. Even in the absence of challenges such as dehydration, haemorrhage or starvation, salt and water are constantly being lost as a consequence of normal, obligatory renal excretory functions, and by the processes of respiration and perspiration. The body has two mechanisms that function to control the consumption and the excretion of water and salt, in order to maintain the optimal bodily content required for good health. The first mechanism involves the production by a part of the brain paraventricular nucleus (PVN) of a hormone called vasopressin that tells the kidney to conserve water. The second mechanism is behavioural, and involves the instincts of thirst and salt appetite that emotionally drive the organism to correct its fluid balance. These mechanisms can go wrong resulting in ill-health. For example, disorders of fluid balance are evident in a substantial proportion of elderly patients admitted to hospital, and dehydration is a frequent cause of morbidity and mortality in old people. An age-related decline in the response to a variety of dehydrating challenges has been reported in humans, and this seems to involve a reduction in thirst and salt appetite, as well as dysregulation of vasopressin production. Another way that disorders of fluid balance can affect wellbeing is as a consequence of an excessive intake of dietary sodium, which is associated with the development of several chronic degenerative diseases, such as cardiovascular disorders, including hypertension. These medical conditions, which are becoming more prevalent as a result of increased life expectancy, progressively decrease life quality and increase the need for medical and social assistance. Epidemiological and experimental studies have suggested that events occurring in utero and during lactation can result in long-term consequences in adult life. Interestingly, both excessive salt intake and dehydration during pregnancy provoke increased salt appetite in adult offspring, which may then impact on long-term health and wellbeing. We have recently produced exciting new evidence that suggests that the PVN is not only involved in the production of vasopressin, but also has a central role in generating the instincts that control the consumption of salt. We thus hypothesise:i) that the PVN integrates hormonal and behavioural responses to salt and imbalance. ii) that these integrative functions are perturbed in old age, resulting in decreased thirst perception, reduced sodium appetite, and altered activity of AVP neurones.iii) that these integrative functions are perturbed by foetal exposure to high salt, resulting in a reprogramming of the set point for adult salt consumption. Or aims are now to decipher the molecular mechanisms by which the PVN controls behavioural (thirst and sodium appetite) and hormonal (AVP synthesis and secretion) mechanisms of salt and water homeostasis. Further, we will find out how these mechanisms go wrong in old age and following foetal programming.

哺乳动物机体的体液处于恒定的流动状态。即使在没有脱水、出血或饥饿等挑战的情况下，由于正常的、强制性的肾排泄功能以及呼吸和出汗过程，盐和水也会不断流失。身体有两种机制来控制水和盐的消耗和排泄，以保持身体健康所需的最佳身体含量。第一种机制涉及到脑室旁核（PVN）的一部分产生一种称为加压素的激素，告诉肾脏保存水分。第二种机制是行为，涉及口渴和盐的本能，这些本能在情感上驱动有机体纠正其液体平衡。这些机制可能出错，导致健康不良。例如，在相当大比例的住院老年患者中，体液平衡紊乱是明显的，脱水是老年人发病和死亡的常见原因。据报道，人类对各种脱水挑战的反应与年龄有关，这似乎涉及口渴和盐食欲的减少，以及加压素产生的失调。体液平衡紊乱可能影响健康的另一种方式是由于过量摄入膳食钠，这与几种慢性退行性疾病的发展有关，例如心血管疾病，包括高血压。由于预期寿命的延长，这些疾病越来越普遍，逐渐降低了生活质量，增加了对医疗和社会援助的需求。流行病学和实验研究表明，在子宫内和哺乳期发生的事件可能对成年生活产生长期影响。有趣的是，怀孕期间过量的盐摄入和脱水都会引起成年后代的盐食欲增加，这可能会影响长期的健康和福祉。我们最近发现了令人兴奋的新证据，表明PVN不仅参与血管加压素的产生，而且在产生控制盐消耗的本能方面也起着核心作用。因此，我们假设：i）PVN整合了对盐和不平衡的激素和行为反应。ii）这些整合功能在老年时受到干扰，导致口渴感降低、钠食欲降低和AVP神经元活性改变。iii）这些整合功能受到胎儿暴露于高盐的干扰，导致成人盐消耗设定点的重新编程。或者现在的目标是破译PVN控制盐和水稳态的行为（口渴和钠食欲）和激素（AVP合成和分泌）机制的分子机制。此外，我们将发现这些机制如何在老年和胎儿编程之后出错。

项目成果

Transcription factor CREB3L1 mediates cAMP and glucocorticoid regulation of arginine vasopressin gene transcription in the rat hypothalamus.

• DOI: 10.1186/s13041-015-0159-1
• 发表时间: 2015-10-26
• 期刊: Molecular brain
• 影响因子: 3.6
• 作者: Greenwood M;Greenwood MP;Mecawi AS;Loh SY;Rodrigues JA;Paton JF;Murphy D
• 通讯作者: Murphy D

Seasonal adaptations of the hypothalamo-neurohypophyseal system of the dromedary camel

• DOI: 10.1371/journal.pone.0216679
• 发表时间: 2019-06-18
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Alim, Fatma Zohra Djazouli;Romanova, Elena V.;Hindmarch, Charles C. T.
• 通讯作者: Hindmarch, Charles C. T.

Regulation of cAMP Responsive Element Binding Protein 3-Like 1 (Creb3l1) Expression by Orphan Nuclear Receptor Nr4a1.

• DOI: 10.3389/fnmol.2017.00413
• 发表时间: 2017
• 期刊: Frontiers in molecular neuroscience
• 影响因子: 4.8
• 作者: Greenwood MP;Greenwood M;Gillard BT;Chitra Devi R;Murphy D
• 通讯作者: Murphy D

The effects of aging on biosynthetic processes in the rat hypothalamic osmoregulatory neuroendocrine system.

• DOI: 10.1016/j.neurobiolaging.2018.01.008
• 发表时间: 2018-05
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Greenwood MP;Greenwood M;Romanova EV;Mecawi AS;Paterson A;Sarenac O;Japundžić-Žigon N;Antunes-Rodrigues J;Paton JFR;Sweedler JV;Murphy D
• 通讯作者: Murphy D

Transcription Factor CREB3L1 Regulates Endoplasmic Reticulum Stress Response Genes in the Osmotically Challenged Rat Hypothalamus.

• DOI: 10.1371/journal.pone.0124956
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Greenwood M;Greenwood MP;Paton JF;Murphy D
• 通讯作者: Murphy D