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Regulatory and functional pathways mediating the control of central osmotic defences by hypothalamic transcription factor CREB3L1

下丘脑转录因子 CREB3L1 介导中枢渗透防御控制的调节和功能途径

基本信息

批准号：
MR/N022807/1
负责人：
David Murphy
金额：
$ 55.09万
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：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FN022807%2F1
关键词：
Regulatory functional pathways mediating control

项目摘要

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 called the hypothalamus, of a hormone called "arginine vasopressin" (AVP) 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. AVP is a peptide hormone that is encoded by the corresponding AVP gene. When an animal becomes dehydrated, AVP is released from the hypothalamus and there is thus a need to make more. Twenty five years ago, we showed that the expression of the AVP gene is hence activated, and more messenger RNA (mRNA) is made from the gene, a process known as "transcription". It is the AVP mRNA that take the information coded by the gene to the cytoplasm of the cell. Here, the information in the mRNA is "translated" into protein. However, the exact molecular mechanisms involved have remained elusive, until now. Using methods that allow us to simultaneously describe the expression of all genes, we identified another gene, called CREB3L1, as being increased in expression in the hypothalamus following dehydration. CREB3L1 is a specialised protein (a "transcription factor") that controls the expression of target genes. We showed that CREB3L1 is expressed in AVP neurones, binds to the promoter region of the AVP gene, and hence drives its expression. Our aims are now to decipher the detailed molecular mechanisms by which CREB3L1 affects gene expression in the hypothalamus, and hence regulates the crucial hormonal processes that govern salt and water homeostasis. We will:*work out which signals tell the hypothalamus to increase the expression of CREB3L1 following dehydration.*find out what other proteins are bound to CREB3L1, which will tell us about upstream factors that regulate CREB3L1, and downstream effectors through which CREB3L1 might exerts its action. *find out what other genes in the AVP cell are regulated by CREB3L1. *determine how CREB3L1 globally affects the elaboration of neuropeptides in the hypothalamus. *embark upon studies that will tell us about the physiological roles of CREB3L1, the proteins that it interacts with and the genes that it regulates. Importantly, these experiments will take place in the physiological integrity of the whole organism. These unique studies will tell us about the mechanisms by which transcription factor protein affects gene expression in the brain, and hence mediates physiological stability.

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。第一种机制涉及大脑中称为下丘脑的部分产生一种名为“精氨酸加压素”（AVP）的激素，该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。 AVP是由相应的AVP基因编码的肽激素。当动物变得脱水时，AVP从下丘脑释放，因此需要制造更多。25年前，我们发现AVP基因的表达因此被激活，更多的信使RNA（mRNA）由该基因产生，这一过程被称为“转录”。AVP mRNA将基因编码的信息带到细胞质中。在这里，mRNA中的信息被“翻译”成蛋白质。然而，直到现在，所涉及的确切分子机制仍然难以捉摸。使用允许我们同时描述所有基因表达的方法，我们发现另一个名为CREB 3L 1的基因在脱水后在下丘脑中表达增加。CREB3L1是一种控制靶基因表达的特异性蛋白质（“转录因子”）。我们发现CREB3L1在AVP神经元中表达，与AVP基因的启动子区结合，从而驱动其表达。我们现在的目标是破译CREB3L1影响下丘脑基因表达的详细分子机制，从而调节控制盐和水稳态的关键激素过程。我们将：* 找出哪些信号告诉下丘脑在脱水后增加CREB3L1的表达。找出CREB3L1结合的其他蛋白质，这将告诉我们调控CREB3L1的上游因子，以及CREB3L1可能发挥作用的下游效应物。* 找出AVP细胞中还有哪些基因受CREB3L1调控。* 确定CREB3L1如何全面影响下丘脑中神经肽的加工。* 着手研究，将告诉我们CREB3L1的生理作用，它与蛋白质相互作用，它调节的基因。重要的是，这些实验将在整个生物体的生理完整性中进行。这些独特的研究将告诉我们转录因子蛋白影响大脑中基因表达的机制，从而介导生理稳定性。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transcription factor Creb3l1 maintains proteostasis in neuroendocrine cells.

DOI：
10.1016/j.molmet.2022.101542
发表时间：
2022-09
期刊：
MOLECULAR METABOLISM
影响因子：
8.1
作者：
Greenwood, Mingkwan;Gillard, Benjamin T.;Farrukh, Rizwan;Paterson, Alex;Althammer, Ferdinand;Grinevich, Valery;Murphy, David;Greenwood, Michael P.
通讯作者：
Greenwood, Michael P.

Effects of long-term dehydration on stress markers, blood parameters, and tissue morphology in the dromedary camel (Camelus dromedarius).

DOI：
10.3389/fvets.2023.1236425
发表时间：
2023
期刊：
Frontiers in veterinary science
影响因子：
3.2
作者：
通讯作者：

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

Osmoadaptive GLP-1R signalling in hypothalamic neurones inhibits antidiuretic hormone synthesis and release.

DOI：
10.1016/j.molmet.2023.101692
发表时间：
2023-04
期刊：
MOLECULAR METABOLISM
影响因子：
8.1
作者：
Greenwood, Michael P.;Greenwood, Mingkwan;Barez-Lopez, Soledad;Hawkins, Joe W.;Short, Katherine;Tatovic, Danijela;Murphy, David
通讯作者：
Murphy, David

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