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，但由此产生的人口变化是一个重大挑战。这是因为老年人的福祉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还不太清楚。然而，越来越多的证据表明，大脑功能障碍涉及广泛的老年慢性疾病。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。大脑中有一个专门的部分叫做下丘脑，它通过产生一种叫做血管加压素（AVP）的激素来控制水的排泄，这种激素告诉肾脏保存水分。AVP是由相应的AVP基因编码的蛋白质激素。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，并产生更多的信使RNA（mRNA）。与此同时，AVP mRNA经历了一种不寻常的修饰; mRNA末端的腺嘌呤（A）残基串-所谓的poly（A）尾-长度从大约200个残基增加到400个残基。重要的是，我们最近发现大鼠AVP mRNA poly（A）尾长随年龄增长而增加。使用允许同时描述所有基因表达的方法，我们确定了另一个基因，称为Caprin 2，一种RNA结合蛋白，在脱水后下丘脑中的表达增加。有超过一千种RNA结合蛋白，但它们的生理作用尚不清楚。我们已经证明Caprin 2在控制液体平衡的大脑机制中起着关键作用。我们发现Caprin 2与AVP mRNA结合并介导poly（A）尾长的增加。重要的是，当我们敲低下丘脑中Caprin 2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Caprin 2的正常功能是以某种方式抑制这种反应。重要的是，我们已经表明，老年大鼠Caprin 2表达增加，与AVP mRNA poly（A）尾长增加平行。然后，我们使用无偏的数学工具，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Caprin 2和编码神经肽强啡肽、血红蛋白-β和受体视蛋白-3的基因之间的调控相互作用。或者现在的目标是破译Caprin 2影响下丘脑基因表达网络的详细分子机制，从而调节控制盐和水稳态的关键激素和生理过程。此外，我们将测试的假设，Caprin 2活性的变化的基础，至少部分，老年的稳态功能障碍。这些独特的研究将告诉我们RNA结合蛋白影响基因表达的机制，从而介导生理稳定性，以及这在老年时是如何出错的。

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.