Trophoblast Intercellular Fusion

滋养层细胞间融合

• 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
• 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

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）：胎盘的生长对人类成功怀孕至关重要。人胎盘的表面是由合体滋养细胞形成的，合体滋养细胞是一种大的多核高度分化细胞，负责将母体循环中的营养物质运输到胎儿循环中。合胞滋养细胞本质上是合胞性的，它不会增殖，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绒毛细胞滋养层和合胞滋养层之间持续的细胞间融合。某些形式的妊娠丢失和宫内生长受限（IUGR）是由滋养细胞间融合的干扰引起的。然而，大多数复发性妊娠丢失和IUGR病例的机制尚不清楚。我们可以合理地预测，细胞间融合缺陷可能是其他形式的妊娠丢失或IUGR的潜在原因。由于滋养层融合的具体过程尚不清楚，因此很难对这一假设进行研究。从许多研究人员的工作来看，滋养细胞间融合似乎依赖于质膜的三个变化：多种细胞间粘附蛋白的外化，一种或多种融合蛋白的表达，以及氨基磷脂的外排。已经研究了融合相关质膜蛋白的一些特定变化，尽管这是以一种零碎的方式完成的。目前还没有关于与细胞间融合相关的质膜蛋白总变化的信息。该R21应用程序旨在利用亚细胞蛋白质组学获得与合胞滋养细胞融合相关的质膜变化的全局信息。通过研究质膜蛋白质组的变化获得的数据将使用全细胞蛋白质组学、免疫组织学、Western blot分析和其他技术来证实。融合相关质膜蛋白的转录将使用定量RT-PCR进行研究。在此基础上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。这些研究将首次确定一个滋养细胞间融合所必需的质膜蛋白家族，并为未来研究这些蛋白与复发性妊娠丢失和IUGR相关的表达改变奠定基础。公共卫生相关性：虽然细胞滋养细胞之间的细胞间融合对人类胎盘的正常生长和功能至关重要，但正常过程和导致妊娠丢失或宫内生长迟缓的过程中的异常却知之甚少。本研究采用亚细胞蛋白质组学等最新技术来描述正常的细胞间融合过程，并为广泛研究可能由融合缺陷引起的妊娠并发症提供基础。