Trophoblast Intercellular Fusion

滋养层细胞间融合

• 批准号: 7656891
• 负责人: NEAL STEWART ROTE
• 金额: $ 23.55万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656891
• 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; Family; Fetal Growth Retardation; Foundations; Future; Genetic Transcription; Growth; Health; Hormones; Human; Individual; Investigation; Knowledge; Lead; Location; Mediating; Membrane; Membrane Proteins; Modeling; Mononuclear; Nature; Nutrient; Phosphatidylethanolamine; Phosphatidylserines; Phospholipids; Placenta; Plasma; Pregnancy; Pregnancy Complications; Pregnancy loss; Process; Production; Proliferating; Proteins; Proteome; Proteomics; 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; public health relevance; 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）：胎盘的生长对于人类成功妊娠至关重要。人胎盘的表面由合体滋养层形成，合体滋养层是一种大的多核高度分化的细胞，负责将营养物质从母体循环运输到胎儿循环。由于本质上是合胞体，合胞体滋养层不增殖，也不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体滋养层之间的持续细胞间融合。某些形式的妊娠丢失和宫内生长受限（IUGR）是由于干扰滋养层细胞融合所致。然而，大多数复发性流产和IUGR病例的机制尚不清楚。这将是合理的预测，有缺陷的细胞间融合可能是其他形式的妊娠丢失或IUGR的根本原因。这是很难调查这一假设，因为滋养层融合的具体过程还没有得到很好的理解。从许多研究人员的工作，它似乎是滋养层融合依赖于质膜的三个变化：多个细胞间粘附蛋白的外化，一个或多个融合蛋白的表达，和氨基磷脂的流出。融合相关的质膜蛋白的一些具体的变化进行了研究，虽然这已经完成了零碎的方式。尚无与细胞间融合相关的相关质膜蛋白总变化的信息。该R21应用程序旨在使用亚细胞蛋白质组学获得与合胞体滋养层融合相关的质膜变化的全球信息。从研究质膜蛋白质组变化中获得的数据将使用全细胞蛋白质组学，免疫组织学，Western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。以后的研究超出了这一建议将确定个别蛋白质的重要性，细胞间的融合过程。这些研究将首次确定一个对滋养层融合至关重要的质膜蛋白家族，并为未来研究与复发性妊娠丢失和IUGR相关的这些蛋白表达的改变奠定基础。 公共卫生关系：尽管细胞滋养层细胞间的融合对于胎盘的正常生长和功能是必不可少的，但对导致妊娠丢失或宫内发育迟缓的正常过程和过程中的畸变却知之甚少。该提案使用最先进的技术，如亚细胞蛋白质组学，来表征正常的细胞间融合过程，并为广泛调查可能由融合缺陷引起的妊娠并发症提供基础。