IMPC: Importance of PABPs in mammalian reproduction and physiology

IMPC：PABP 在哺乳动物生殖和生理学中的重要性

• 批准号: MR/P02419X/1
• 负责人: Nicola Gray
• 金额: $ 5.03万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP02419X%2F1
• 关键词: IMPC; Importance; PABPs; mammalian; reproduction

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.

构成我们细胞的蛋白质是由充当遗传蓝图的基因编码的。存储在基因中的信息被表达或解码，以通过称为基因表达的多步骤过程产生蛋白质。一个关键步骤是将遗传密码复制到用于制造蛋白质（mRNA 翻译）的模板 (mRNA)。因此，mRNA 翻译的调节和模板的破坏（稳定性）是确保细胞和生物体需要在正确的时间、地点以正确的量制造蛋白质的关键步骤。当 mRNA 翻译和稳定性得不到适当调节时，可能会导致多种疾病，包括癌症、代谢、神经和生殖疾病。 Poly(A) 结合蛋白是基因表达途径多个步骤的中心调节因子，包括 mRNA 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）在全身的许多细胞类型中产生，其中两个主要（ePABP）/仅（tPABP）在生殖组织中表达。虽然蛋白质的功能已在细胞中得到广泛研究，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。全面了解是一个长期目标，但我们和其他人的工作已经证实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，我们发现一名家庭成员 (ePABP) 对于产卵能力至关重要，这一点很重要，因为全世界大约 10-15% 的夫妇患有不孕症。我们发现第二个成员 (PABP4) 也会影响女性生育能力，但在这种情况下，这是由于怀孕后期的问题导致子宫内生长问题（宫内生长受限）和晚期胎儿死亡（死产）。宫内发育不良会使人类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，在英国，死产影响的婴儿数量是唐氏综合症婴儿的 5 倍 (1/200)。我们还发现 PABP4 在调节脂肪和葡萄糖水平方面很重要，尤其是在高脂肪（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，而在英国 390 万名糖尿病患者中，90% 的人患有 II 型糖尿病。这些结果说明了进一步研究这个家族的重要性。大量证据使我们相信 ePABP 和 PABP4 对于体内的其他过程也很重要，但到目前为止，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，并相互替代。因此，我们的目标是使用遗传方法来克服这一限制，以确定它们参与了哪些额外过程，例如男性生育能力以及我们迄今为止观察到的影响（例如代谢）是否变得更糟。这是了解该家族对人类疾病的全面贡献并探索其作为治疗靶点的潜力的必要垫脚石。

项目成果

DAZL regulates mRNA deadenylation independently of translation in germ cells

• DOI: 10.1101/2021.02.02.429436
• 发表时间: 2021-02
• 期刊: bioRxiv
• 作者: Richard W. P. Smith;B. Gorgoni;Zoe C. Johnston;William A. Richardson;Kelsey Grieve;Ross C. Anderson;N. Gray