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Poly(A)-binding proteins highlight the importance of regulated mRNA translation and stability in determining a functional materno-fetal interface

Poly(A) 结合蛋白强调了调节 mRNA 翻译和稳定性在确定功能性母胎界面中的重要性

基本信息

批准号：
MR/J003069/1
负责人：
Nicola Gray
金额：
$ 193.64万
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：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FJ003069%2F1
关键词：
Poly binding proteins highlight importance

项目摘要

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, with one of the critical steps in this pathway being mRNA translation. In order to function properly, cells and organisms need to make proteins at the right time, place and in the correct amount. Thus it is critical that mRNA translation is carefully regulated, with improper control leading to a wide variety of diseases including cancer, metabolic, neurological and reproductive disorders.Poly(A)-binding protein (PABP) 1 is a central regulator of multiple steps in the gene expression pathway, including mRNA translation. Mammals contain five genes belonging to the PABP family, two of which (PABP1 and PABP4) are produced in many cell types throughout the body. Although PABP1 has been extensively studied, little is known about the potential roles of PABP1, or other family members, in human health. However, we have recently found that an absence of PABP4 severely reduces mammalian fertility. This appears to be due to problems with the mother which lead to fetal death during the later stages of pregnancy. Interestingly, we see that live births are frequently small suggesting growth problems whilst in the womb (intrauterine growth restriction). Poor intrauterine growth predisposes human babies to health problems in adulthood including cardiovascular disease, stroke and type II diabetes. These important observations suggest that we have a unique opportunity to study the underlying causes of a spectrum of pregnancy complications including stillbirth, late miscarriage and intrauterine growth restriction. Nearly 3 million third-trimester stillbirths occur worldwide each year, with the UK having a higher rate (1 in 200) than almost every other high-income country. Research has shown that stillbirth can be caused by problems with the placenta, the umbilical cord or by infections, although in many cases the reasons why these problems arose is not understood. Moreover, up to 30% of stillbirths have no obvious cause, emphasising the need for research in this area. Our research aims to shed light on these issues by performing a detailed analysis of the functions and regulatory targets of PABP4, of which little is presently known, and by further investigating the cellular processes that fail to function normally in the absence of PABP4. Importantly, this will be paralleled by an investigation of PABP4 in human reproductive tissues. Taken together this work presents a unique opportunity to understand the pathways and mechanisms that lead to stillbirth and poor intrauterine growth. This forms the first step towards providing answers to couples that suffer such loss, and in the longer term may identify novel prognostic markers for pregnancy failure that could indicate the need for medical intervention. Ultimately it may offer avenues for therapeutic intervention prior to or during pregnancy.

构成我们细胞的蛋白质是由基因编码的，这些基因是遗传蓝图。储存在基因中的信息被表达或解码，通过称为基因表达的多步骤过程产生蛋白质，该途径中的关键步骤之一是mRNA翻译。为了正常运作，细胞和生物体需要在正确的时间，地点和正确的数量制造蛋白质。因此，mRNA翻译的调控是至关重要的，如果调控不当，会导致多种疾病，包括癌症、代谢、神经和生殖系统疾病。多聚腺苷酸结合蛋白（PABP）1是基因表达途径中多个步骤（包括mRNA翻译）的中心调控因子。哺乳动物含有属于PABP家族的五个基因，其中两个（PABP 1和PABP 4）在整个身体的许多细胞类型中产生。虽然PABP 1已被广泛研究，但对PABP 1或其他家族成员在人类健康中的潜在作用知之甚少。然而，我们最近发现PABP 4的缺乏严重降低了哺乳动物的生育能力。这似乎是由于母亲的问题，导致胎儿在怀孕后期死亡。有趣的是，我们看到活产婴儿通常很小，这表明在子宫内存在生长问题（宫内生长受限）。宫内发育不良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。这些重要的观察结果表明，我们有一个独特的机会来研究一系列妊娠并发症的根本原因，包括死胎，晚期流产和宫内生长受限。全世界每年有近300万例晚期死胎，英国的比例（1/200）几乎高于其他所有高收入国家。研究表明，死胎可能是由胎盘、脐带或感染的问题引起的，尽管在许多情况下，这些问题出现的原因尚不清楚。此外，高达30%的死产没有明显的原因，强调了在这一领域进行研究的必要性。我们的研究旨在通过对PABP 4的功能和调控靶点进行详细分析来阐明这些问题，目前对此知之甚少，并通过进一步研究在PABP 4缺乏的情况下无法正常发挥功能的细胞过程。重要的是，这将通过对PABP 4在人类生殖组织中的研究来证实。总之，这项工作提供了一个独特的机会，了解途径和机制，导致死胎和宫内生长不良。这是为遭受这种损失的夫妇提供答案的第一步，从长远来看，可能会发现新的妊娠失败的预后标志物，这些标志物可能表明需要进行医疗干预。最终，它可能为怀孕前或怀孕期间的治疗干预提供途径。