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Investigating the human myometrial acetylome and identifying potential new targets for treating preterm labour

研究人类子宫肌层乙酰组并确定治疗早产的潜在新靶点

基本信息

批准号：
MR/L009560/1
负责人：
Nick Europe-Finner
金额：
$ 92.85万
依托单位：
Newcastle University
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FL009560%2F1
关键词：
Investigating human myometrial acetylome identifying

项目摘要

Preterm birth occurs in >50,000 cases per annum in the UK and is still the major cause of neonatal mortality and morbidity in the UK. Preterm babies that survive do so with an elevated risk of long-term physical or mental handicap. Globally, the WHO estimate that up to 15 million births per annum occur prematurely with approximately 1 million neonatal deaths. The development of better therapeutics in managing preterm birth, therefore, is a prime research aim that serves to tackle the considerable health and socio-economic impacts of this disorder. A major contributor to the incidence of preterm birth is premature activation of uterine contractions, even in the absence of other clinical risk associations such as infection, yet there still is no broadly efficient therapeutic treatment free of risk factors for the mother and/or neonate. At present, our understanding of the mechanisms that control activation of the uterus at term or preterm is weak compared to other organ systems and this is reflected in our inability to prescribe drugs that limit premature uterine contractility without jeopardising neonatal outcome. This project seeks to address these issues.Recent technical and experimental advances in high throughput proteomics have made us aware of an expanding range of protein modifications that may regulate cell function. Published evidence from our laboratory has indicated that myofilament-associated protein acetylation is an important mechanism for regulating human myometrial contractility. Drugs which act to increase protein acetylation by inhibiting lysine deacetylases (KDACs) not only reduce human myometrial contractility in vitro but also delay uterine activation in an animal model of preterm labour whilst improving neonatal survival. In the present study we will employ advanced proteomic techniques to identify proteins that are targets for acetylation in these processes. Utilising a cross-disciplinary approach, encompassing scentific and clinical expertise, and experimentation on human ex vivo biopsies in alliance with in vivo animal model of preterm labour, we will provide novel identification of changes in myometrial protein acetylation, including the identification of individual acetylation sites, with treatment by KDAC inhibition or lysine acetylase (KAT) activation. In concert, we will establish the ability of KDAC inhibition or KAT activation to delay experimentally-induced preterm labour and improve neonatal survival and outcome. As these are the defining aspirations of developing any new tocolytic drugs, our data will not only inform us of novel molecular mechanisms involved in regulating term and preterm labour, but will also inform us of promising protein targets for development of future therapeutics for preterm labour. Beyond the immediate scientific and clinical research practitioners interested in pregnancy and pregnancy complications, this work will also provide a publicly-available dataset with a broad scale assessment of human and guinea pig cell protein acetylation which will be of interest to comparative biologists and proteomic bioinformaticians.

在英国，早产每年发生在> 50，000例中，并且仍然是英国新生儿死亡和发病的主要原因。存活下来的早产儿患长期身体或精神障碍的风险更高。世卫组织估计，全球每年有多达1500万例早产，约有100万例新生儿死亡。因此，开发更好的治疗方法来管理早产是一个主要的研究目标，旨在解决这种疾病对健康和社会经济的重大影响。早产发生率的一个主要因素是子宫收缩的过早激活，即使在没有其他临床风险相关性（如感染）的情况下，但仍然没有广泛有效的治疗方法来消除母亲和/或新生儿的风险因素。目前，与其他器官系统相比，我们对控制足月或早产时子宫激活的机制的理解是薄弱的，这反映在我们无法开出限制早产子宫收缩力而不危及新生儿结局的药物。本项目旨在解决这些问题。高通量蛋白质组学的最新技术和实验进展使我们意识到可能调节细胞功能的蛋白质修饰范围不断扩大。我们实验室已发表的证据表明，肌张力相关蛋白乙酰化是调节人类子宫肌层收缩力的重要机制。通过抑制赖氨酸脱乙酰酶（KDAC）来增加蛋白乙酰化的药物不仅在体外降低人子宫肌层收缩性，而且在早产动物模型中延迟子宫激活，同时改善新生儿存活。在本研究中，我们将采用先进的蛋白质组学技术，以确定蛋白质的乙酰化在这些过程中的目标。利用跨学科的方法，包括科学和临床专业知识，以及与早产的体内动物模型联合的人类离体活检实验，我们将提供子宫肌层蛋白乙酰化变化的新鉴定，包括鉴定单个乙酰化位点，通过KDAC抑制或赖氨酸乙酰化酶（KAT）激活进行治疗。同时，我们将确定KDAC抑制或KAT激活延迟实验诱导的早产并改善新生儿存活率和结局的能力。由于这些是开发任何新的保胎药物的定义愿望，我们的数据不仅将告知我们参与调节足月和早产的新分子机制，而且还将告知我们有前途的蛋白质靶点，用于开发未来的早产治疗药物。除了对妊娠和妊娠并发症感兴趣的直接科学和临床研究从业者之外，这项工作还将提供一个公开的数据集，对人类和豚鼠细胞蛋白乙酰化进行广泛的评估，这将是比较生物学家和蛋白质组学生物信息学家感兴趣的。