Trophoblast Intercellular Fusion

滋养层细胞间融合

基本信息

批准号：
7471713
负责人：
NEAL STEWART ROTE
金额：
$ 19.63万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-10 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7471713
关键词：
Adhesions Antiphospholipid Antibodies Antiphospholipid Syndrome Arts Blood Blood Circulation Cell Membrane Proteins Cell Nucleus Cell Proliferation Cell Size Cell Surface Proteins Cell membrane Cell model Cell surface Cells Characteristics Chimeric Proteins Choriocarcinoma Complex DNA Sequence Rearrangement Data Defect Down Syndrome Event Facility Construction Funding Category Family Fetal Growth Retardation Foundations Future Genetic Transcription Growth Health Hormones Human Individual Investigation Knowledge Lead Location Mediating Membrane Membrane Proteins Modeling Mononuclear Nature Numbers Nutrient Phosphatidylethanolamine Phosphatidylserines Phospholipids Placenta Plasma Pregnancy Pregnancy Complications Pregnancy loss Process Production Proliferating Proteins Proteome Proteomics Public Health Recurrence Research Personnel Reverse Transcriptase Polymerase Chain Reaction Risk Role Signal Transduction Spontaneous abortion Surface Syncytiotrophoblast Techniques Testing Time Trisomy Villous Western Blotting Work base cytotrophoblast design fetal phosphatidylethanolamine protein expression success tool trophoblast

项目摘要

DESCRIPTION (provided by applicant): Growth of the placenta is essential for a successful human pregnancy. The surface of the human placenta is formed by the syncytiotrophoblast, which is a large multinucleate highly differentiated cell that is responsible for transport of nutrients from the maternal to fetal circulations. Being syncytial in nature, the syncytiotrophoblast does not proliferate and does not independently increase cell size. The growth of the placental surface is dependent on continuous intercellular fusion between the underlying proliferative villous cytotrophoblast layer and the syncytiotrophoblast. Some forms of pregnancy loss and intrauterine growth restriction (IUGR) result from interference with intertrophoblast fusion. However, the mechanism underlying most cases of recurrent pregnancy loss and IUGR is unknown. It would be reasonable to predict that defective intercellular fusion may be the underlying cause of other forms of pregnancy loss or IUGR. It is difficult to investigate this hypothesis because the specific process by which trophoblast fuse is not well understood. From the work of many investigators it appears that intertrophoblast fusion is dependent on three changes in the plasma membrane: the externalization of multiple intercellular adhesion proteins, the expression of one or more fusion proteins, and efflux of aminophospholipids. A few specific changes in fusion-related plasma membrane proteins have been investigated, although this has been done in a piece-meal fashion. There is no information on the total change in relevant plasma membrane proteins related to intercellular fusion. This R21 application is designed to obtain global information about plasma membrane changes related to syncytiotrophoblast fusion using subcellular proteomics. The data obtained from studying changes in the plasma membrane proteome will be confirmed using whole cell proteomics, immunohistology, Western blot analysis, and other techniques. The transcription of fusion- related plasma membrane proteins will be investigated using quantitative RT-PCR. Later studies beyond this proposal will ascertain the importance of individual proteins to the intercellular fusion process. These studies will, for the first time, identify a family of plasma membrane proteins that are essential for intertrophoblast fusion and form the basis for future studies on alterations of the expression of these proteins related to recurrent pregnancy loss and IUGR. PUBLIC HEALTH RELEVANCE: Although intercellular fusion between cytotrophoblast cells is essential for normal growth and function of the human placenta, the normal process and aberrations in that process leading to pregnancy loss or intrauterine growth retardation are understood very little. This proposal uses state-of-the-art techniques, such as subcellular proteomics, to characterize the normal intercellular fusion process and provide a foundation for extensive investigations of pregnancy complications that may arise from defective fusion.

描述（由申请人提供）：胎盘的生长对于人类成功怀孕至关重要。人类胎盘的表面由合体滋养层形成，合体滋养层是一种大型多核高度分化细胞，负责将营养物质从母体输送到胎儿循环。由于本质上是合体，合体滋养层不会增殖，也不会独立地增加细胞大小。胎盘表面的生长依赖于下面的增殖性绒毛细胞滋养层和合体滋养层之间的连续细胞间融合。某些形式的流产和宫内生长受限（IUGR）是由于滋养层融合受到干扰造成的。然而，大多数复发性流产和 IUGR 病例的机制尚不清楚。可以合理地预测，细胞间融合缺陷可能是其他形式的流产或 IUGR 的根本原因。研究这一假设很困难，因为滋养层融合的具体过程尚不清楚。从许多研究人员的工作来看，滋养层间融合似乎依赖于质膜的三种变化：多种细胞间粘附蛋白的外化、一种或多种融合蛋白的表达以及氨基磷脂的流出。已经研究了融合相关质膜蛋白的一些具体变化，尽管这是以零碎的方式完成的。没有关于与细胞间融合相关的质膜蛋白的总变化的信息。此 R21 应用程序旨在使用亚细胞蛋白质组学获取与合体滋养层融合相关的质膜变化的全局信息。通过研究质膜蛋白质组变化获得的数据将使用全细胞蛋白质组学、免疫组织学、蛋白质印迹分析和其他技术进行确认。将使用定量 RT-PCR 研究融合相关质膜蛋白的转录。除此提议之外的后续研究将确定单个蛋白质对细胞间融合过程的重要性。这些研究将首次鉴定出对滋养层间融合至关重要的质膜蛋白家族，并为未来研究与复发性流产和 IUGR 相关的这些蛋白的表达变化奠定基础。公共健康相关性：尽管细胞滋养层细胞之间的细胞间融合对于人类胎盘的正常生长和功能至关重要，但该过程中导致流产或宫内生长迟缓的正常过程和畸变却知之甚少。该提案使用最先进的技术，例如亚细胞蛋白质组学，来表征正常的细胞间融合过程，并为广泛研究因融合缺陷可能引起的妊娠并发症奠定基础。