The role of hypothalamic RNA binding protein Caprin2 in osmoregulatory dysfunction in old age

到2050年，25%的人口将超过65岁。虽然寿命的大幅增加值得庆祝，但由此带来的人口结构变化是一个重大挑战。这是因为老年的幸福和健康并没有随着寿命的延长而成比例地改善。老年人身体系统恶化的原因尚不清楚。然而，越来越多的证据表明，大脑功能障碍与老年的一系列慢性病有关。例如，在住院的老年患者中，相当大比例的患者明显存在液体平衡障碍，脱水是老年人发病和死亡的常见原因。大脑的一个特殊部分，称为下丘脑，通过产生一种名为加压素(AVP)的荷尔蒙来控制水分的排泄，这种荷尔蒙告诉肾脏保存水分。AVP是一种由相应的AVP基因编码的蛋白质激素。当动物脱水时，AVP从下丘脑释放出来，因此需要制造更多的AVP。25年前，我们发现AVP基因的表达因此被激活，并产生更多的信使RNA(MRNA)。与此同时，AVP mRNA经历了一个不寻常的修饰；mRNA末端的一串腺嘌呤(A)残基-所谓的聚(A)尾巴-从大约200个残基增加到400个残基。重要的是，我们最近发现，在大鼠中，AVP mRNA Poly(A)尾长随着年龄的增长而增加。使用可以同时描述所有基因表达的方法，我们发现了另一个基因，称为Caprin2，一种RNA结合蛋白，在脱水后在下丘脑中表达增加。有一千多种RNA结合蛋白，但它们的生理作用尚不清楚。我们已经证明Caprin2在控制液体平衡的大脑机制中起着关键作用。我们发现Caprin2与AVP mRNA结合，并介导Poly(A)尾长的增加。重要的是，当我们下调Caprin2在下丘脑的表达时，我们改变了对脱水刺激的反应--更多的AVP被释放到血液中，这表明Caprin2的正常功能是以某种方式抑制这种反应。重要的是，我们已经证明，随着大鼠年龄的增加，Caprin2的表达增加，同时AVP mRNA Poly(A)尾长增加。然后，我们使用无偏见的数学工具，使用全球基因表达数据来预测基因相互作用。我们测试了这个基因网络，并验证了Caprin2与编码神经肽强啡肽、血红蛋白-β和受体Opsin-3的基因之间的调控相互作用。现在的目标是破译Caprin2影响下丘脑基因表达网络的详细分子机制，从而调节控制盐分和水分动态平衡的关键激素和生理过程。此外，我们将检验这样一种假设，即Caprin2活性的变化至少部分地是老年人体内平衡功能障碍的基础。这些独特的研究将告诉我们RNA结合蛋白影响基因表达从而调节生理稳定性的机制，以及这种机制在老年是如何出错的。

By 2050, 25% of the population will be over 65. Whilst this dramatic increase in lifespan should be celebrated, the resultant demographic change represents a major challenge. This is because wellbeing and health in old age has not improved proportionally with longevity. The reasons why bodily systems deteriorate in the elderly is not well understood. However, there is growing evidence that brain dysfunction is involved in a wide range of chronic conditions of old age. 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. A specialised part of the brain called the hypothalamus controls the excretion of water through the production of a hormone called vasopressin (AVP) that tells the kidney to conserve water. AVP is a protein 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. At the same time, the AVP mRNA undergoes an unusual modification; the string of adenine (A) residues at the end of the mRNA - the so-called poly(A) tail - increases in length from around 200 to 400 residues. Importantly, we have recently shown that the AVP mRNA poly(A) tail length increases with age in rats. Using methods that allow is to simultaneously describe the expression of all genes, we identified another gene, called Caprin2, an RNA binding protein, as being increased in expression in the hypothalamus following dehydration. There are over a thousand RNA binding proteins, but their physiological roles are not understood. We have shown that Caprin2 has a pivotal role in the brain mechanisms that control fluid balance. We showed that Caprin2 binds to the AVP mRNA and mediates the increase in poly(A) tail length. Importantly, when we knockdown expression of Caprin2 in the hypothalamus, we alter the response to a dehydrating stimulus - more AVP is released into the blood, suggesting that the normal function of Caprin2 is to inhibit this in some way. Importantly, we have shown that old age in rats results in an increase in Caprin2 expression, in parallel with the increase in AVP mRNA poly(A) tail length. We then used unbiased mathematical tools that use global gene expression data to predict gene interactions. We tested this gene network and validated regulatory interactions between Caprin2 and the genes encoding the neuropeptide dynorphin, haemoglobin-beta and the receptor Opsin-3. Or aims are now to decipher the detailed molecular mechanisms by which Caprin2 affects a network of gene expression in the hypothalamus, and hence regulates the crucial hormonal and physiological processes that govern salt and water homeostasis. Further, we will test the hypothesis that changes in Caprin2 activity underlie, at least in part, the homeostatic dysfunction of old age. These unique studies will tell us about the mechanisms by which an RNA binding protein affect gene expression and hence mediate physiological stability, and how this goes wrong in old age.