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）：胎盘的生长对于成功的人类怀孕至关重要。人胎盘的表面是由合成型胞素细胞形成的，该细胞细胞是一个大型多核细胞，高度分化的细胞，负责从母体到胎儿循环的养分运输。本质上是合成性的，合成型成素细胞不会增殖，也不会独立增加细胞大小。胎盘表面的生长取决于潜在的增殖性细胞增生性细胞增生层和合成型细胞细胞之间的连续细胞间融合。某些形式的妊娠丧失和宫内生长限制（IUGR）是由于干扰跨层间融合而导致的。但是，大多数复发妊娠丧失和IUGR的机制尚不清楚。可以合理地预测有缺陷的细胞间融合可能是其他形式的怀孕丧失或IUGR的根本原因。很难研究这一假设，因为滋养细胞融合的特定过程尚不清楚。从许多研究者的工作中看来，间层间融合取决于质膜的三种变化：多个细胞间粘附蛋白的外部化，一种或多种融合蛋白的表达以及氨基磷脂的外排。已经研究了与融合相关的质膜蛋白的一些特定变化，尽管这是以碎片方式进行的。没有有关与细胞间融合有关的相关质膜蛋白总变化的信息。该R21应用旨在获取有关使用亚细胞蛋白质组学与合成肌细胞融合相关的质膜变化的全球信息。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证实。将使用定量RT-PCR研究融合相关的质膜蛋白的转录。除此提案以外的后期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质膜蛋白的家族，这些质子蛋白是间质细胞融合至关重要的，并为将来研究这些蛋白质表达的变化构成基础，这些蛋白质与复发性妊娠丧失和IUGR有关。 公共卫生相关性：尽管细胞增生细胞细胞之间的细胞间融合对于人体胎盘的正常生长和功能至关重要，但该过程中的正常过程和畸变导致妊娠丧失或宫内内生长延迟的理解很少。该提案使用最新的技术，例如亚细胞蛋白质组学，以表征正常的细胞间融合过程，并为对妊娠并发症的广泛研究奠定了基础，这些并发症可能是由于缺陷融合而引起的。