IMPC: Importance of PABPs in mammalian reproduction and physiology

构成我们细胞的蛋白质是由作为遗传蓝图的基因编码的。储存在基因中的信息被表达或解码，通过一个称为基因表达的多步骤过程来产生蛋白质。其中一个关键步骤是将遗传密码复制到模板(信使核糖核酸)上，该模板用于制造蛋白质(信使核糖核酸翻译)。因此，调节mRNA翻译和破坏模板(稳定性)是确保细胞和生物体需要在正确的时间、地点和正确的量制造蛋白质的关键步骤。当mRNA的翻译和稳定性没有得到适当的调控时，可能会导致多种疾病，包括癌症、新陈代谢、神经和生殖障碍。Poly(A)结合蛋白是基因表达途径中多个步骤的中央调节因子，包括mRNA的翻译和稳定性。哺乳动物包含四个与该家族成员非常相似的基因，其中两个(PABP1和PABP4)在全身许多细胞类型中产生，另两个主要(EPABP)/仅(TPABP)在生殖组织中表达。虽然蛋白质的功能已经在细胞中得到了广泛的研究，但它们在体内的作用仍然不太清楚，这意味着需要对整个有机体进行研究。获得完整的情况是一个长期的目标，但我们和其他人的工作已经确定，它们在与人类生殖和代谢紊乱相关的过程中发挥着重要作用。总的来说，我们发现一个家庭成员(EPABP)对于产卵能力是必不可少的，这一点很重要，因为全世界大约有10%-15%的夫妇患有不孕症。我们发现第二个成员(PABP4)也影响女性的生育力，但在这种情况下，它是由于怀孕后期的问题导致子宫中的生长问题(宫内生长受限)和晚期胎儿死亡(死产)。在英国，胎儿宫内发育不良使婴儿在成年后容易出现健康问题，包括心血管疾病、中风和II型糖尿病，死产对婴儿的影响是唐氏综合症的5倍(1/200)。我们还发现，PABP4在调节脂肪和血糖水平方面很重要，特别是在高脂肪(垃圾食品)饮食中，这意味着它可能构成肥胖和II型糖尿病之间重要联系的一部分，在英国390万糖尿病患者中，II型糖尿病占90%。这些结果说明了进一步研究该家族的重要性。大量证据使我们相信，ePABP和PABP4对体内的其他过程也很重要，到目前为止，我们可能错过了这些影响，因为这两种蛋白质同时存在于同一细胞内，相互替代。因此，我们的目标是使用遗传方法来克服这一限制，以确定他们参与了哪些额外的过程，例如男性生育能力，以及我们迄今观察到的影响(例如代谢)是否会变得更糟。这是了解该家庭对人类疾病的全部贡献并探索其作为治疗目标的潜力所必需的踏脚石。

The proteins that make up our cells are encoded by genes that serve as a genetic blueprint. The information stored in genes is expressed, or decoded, to produce proteins by a multi-step process known as gene expression. One key step is when the genetic code is copied to a template (mRNA) which is used to make proteins (mRNA translation). Thus the regulation of mRNA translation and destruction of the template (stability) are keys steps to making sure that cells and organisms need to make proteins at the right time, place and in the correct amount. When mRNA translation and stability are not properly regulated this can lead to a wide variety of diseases including cancer, metabolic, neurological and reproductive disorders. Poly(A)-binding proteins are central regulator of multiple steps in the gene expression pathway, including mRNA translation and stability. Mammals contain four very similar genes for members of this family, two of which (PABP1 and PABP4) are produced in many cell types throughout the body and two of which are mainly (ePABP)/only (tPABP) expressed in reproductive tissues. Whilst the functions of proteins have been extensively studied in cells, their roles in within the body remains less clear meaning that whole organism studies are required. Gaining a complete picture is is a long term goal, but work by ourselves and others have already established that they have important roles in processes associated with human reproductive and metabolic disorders. Collectively, we have found that one family member (ePABP) is essential for the ability to make eggs, this is important as roughly 10-15% of couples worldwide suffer from infertility. We have found that a second member (PABP4) also affects female fertility, but in this case it is due to problems during the later stages of pregnancy leading to growth problems whilst in the womb (intrauterine growth restriction) and late fetal death (stillbirth). Poor intrauterine growth predisposes human babies to health problems in adulthood including cardiovascular disease, stroke and type II diabetes, and stillbirth affects 5 times more babies than Down's syndrome in the UK (1/200). We have also found that PABP4 is important in regulating fat and glucose levels, especially on high fat (junk food) diets, meaning it may form part of the important link between obesity and type II diabetes, which accounts for 90% of the 3.9 million people affected by diabetes in the UK. These results illustrate the importance of further studying this family. Numerous lines of evidence lead us to believe that ePABP and PABP4 are also important for other processes within the body, and we may have missed these effects so far, due to both proteins being present within the same cell at the same time, substituting for one another. Thus we aim to use genetic methods to overcome this limitation in order to identify what additional processes they are involved in, for instance male fertility and whether the effects (e.g. metabolic) we have observed thus far get worse. This is a necessary stepping stone to understanding the full spectrum of the contribution of this family to human disease and to exploring their potential as a therapeutic target.