权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Differential expression and function of the human chorionic gonadotropin beta subunits

人绒毛膜促性腺激素β亚基的差异表达和功能

基本信息

批准号：
225144127
负责人：
Professor Dr. Kurt Engeland, since 2/2016
金额：
--
依托单位：
Abteilung Molekulare Onkologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/225144127?language=en
关键词：
Differential expression function human chorionic

项目摘要

Human chorionic gonadotropin is known as a central pregnancy-supporting hormone playing an essential role in early human pregnancy. Besides its classical endocrine function in supporting corpus luteum survival to maintain progesterone production several new paracrine roles promoting embryo implantation and placentation have been described lately. hCG is active as a highly glycosylated heterodimer. There are six genes coding for the hCG beta-subunit (CGB) with CGB3, 5, 7 and 8 being most relevant in pregnancy. CGB3, 5 and 8 encode identical proteins secreted by the placenta and some tumour types. CGB7 differs in only three amino acids from CGB3/5/8 but shows a substantially different expression pattern. In a recent report I demonstrated that the transcription factor p53 selectively induces CGB7 expression by binding directly to a consensus site in the CGB7 promoter region. Additionally, recent findings from our group provide evidence that CGB7 is produced by the secretory endometrium during the implantation window. This observation emphasizes the importance of the maternally-produced CGB for the first time. The different expression patterns of the CGB variants raise the question of functional differences which has not yet been addressed. In the proposed project I wish to investigate whether CGB7 and CGB3/5/8 actually exert different functions. hCG is known to modulate the maternal immune response. Hence, the influence of the CGB isoforms on peripheral blood mononuclear cells will be studied. Additionally, CGB7 and CGB3/5/8 will be compared with regard to their impact on the cell cycle, apoptosis and invasion as well as their signal transduction properties. Considering that glycosyl groups constitute about 30 % of the hCG molecular weight and that glycosylation is essential for hCG function, one focus of the proposed work will be on identifying the glycosylation patterns of the different CGB isoforms. According to the hypothesis we developed from the latest results, CGB7 synthesised by maternal tissue supports implantation and thus can serve as an implantation marker. To determine the clinical significance of hCG in more detail, the association of CGB with successful embryo implantation will be analysed. For this purpose, endometrial paraffin sections of patients from the Centre for Reproductive Medicine at the University of Leipzig will be employed. For immunohistochemical expression analysis of the CGB variants, monoclonal antibodies specific to the individual CGB variants will be developed. The proposed experiments aim to address the question what functional differences result from the differences in amino acid sequence and glycosylation patterns of CGB7 versus CGB3/5/8. The results are fundamental for understanding the events during early human pregnancy and have the potential to improve diagnosis and possibly even therapy in reproductive medicine.

人绒毛膜促性腺激素是一种中枢性的妊娠支持激素，在人类早期妊娠中起着重要作用。除了支持黄体存活以维持孕酮产生的经典内分泌功能外，最近还描述了几种新的旁分泌作用，促进胚胎着床和胎盘形成。hCG作为高度糖基化的异二聚体是有活性的。有六个基因编码人绒毛膜促性腺激素β亚基（CGB），其中CGB 3、5、7和8与怀孕最相关。CGB 3、5和8编码由胎盘和某些肿瘤类型分泌的相同蛋白质。CGB 7与CGB 3/5/8仅在三个氨基酸上不同，但显示出实质上不同的表达模式。在最近的一份报告中，我证明了转录因子p53通过直接结合CGB 7启动子区域的共有位点来选择性地诱导CGB 7表达。此外，我们小组最近的研究结果提供了证据表明，CGB 7是由分泌期子宫内膜在植入窗口期产生的。这一观察结果首次强调了母体产生的CGB的重要性。CGB变体的不同表达模式提出了尚未解决的功能差异问题。在建议的项目中，我希望调查CGB 7和CGB 3/5/8是否实际上发挥不同的功能。已知hCG调节母体免疫应答。因此，将研究CGB同种型对外周血单核细胞的影响。此外，将比较CGB 7和CGB 3/5/8对细胞周期、凋亡和侵袭的影响以及它们的信号转导特性。考虑到糖基占hCG分子量的约30%，并且糖基化对于hCG功能是必不可少的，所提出的工作的一个重点将是鉴定不同CGB同种型的糖基化模式。根据我们从最新结果发展的假设，由母体组织合成的CGB 7支持植入，因此可以作为植入标记物。为了更详细地确定hCG的临床意义，将分析CGB与成功胚胎植入的关联。为此，将采用莱比锡大学生殖医学中心患者的子宫内膜石蜡切片。对于CGB变体的免疫组织化学表达分析，将开发对单个CGB变体具有特异性的单克隆抗体。所提出的实验旨在解决CGB 7与CGB 3/5/8的氨基酸序列和糖基化模式的差异导致的功能差异的问题。这些结果对于了解人类早期妊娠期间的事件至关重要，并有可能改善生殖医学的诊断甚至治疗。