Apoptosis and Trophoblast Fusion

细胞凋亡和滋养层融合

• 批准号: 7581757
• 负责人: NEAL STEWART ROTE
• 金额: $ 39.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-27 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7581757
• 关键词: Actins; Affect; Antibodies; Apoptosis; Apoptotic; Area; Arts; Caspase; Cell Proliferation; Cell membrane; Cells; Cessation of life; Child; Chimeric Proteins; Choriocarcinoma; Conflict (Psychology); DNA Sequence Rearrangement; Data; Development; Elements; Family; Fetal Growth Retardation; Foundations; Fusion Protein Expression; G1 Arrest; Gene Silencing; Genetic; Genetic Transcription; Goals; Growth; Human; Human Chorionic Gonadotropin; Individual; Investigation; Knowledge; Lead; Link; Maintenance; Mediating; Membrane; Messenger RNA; Modeling; Nature; Newborn Infant; Nutrient; Participant; Pathway interactions; Peptides; Personal Satisfaction; Phosphatidylserines; Phospholipids; Photoaffinity Labels; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Labor; Process; Production; Progesterone; Proteins; Resistance; Role; Signal Transduction; Spontaneous abortion; Surface; Syncytiotrophoblast; Technology; Testing; Time; Translations; Villous; Work; base; caspase 14; caspase-3; caspase-8; cell type; corpus luteum; cytotrophoblast; fetal; in vitro Model; inhibitor/antagonist; interest; pro-apoptotic protein; pro-caspase-8; reconstruction; research study; theories; trophoblast

Common pregnancy complications, such as intrauterine growth restriction (IUGR) and miscarriage, are strongly associated with abnormal development of the placenta. Defective placentation may result from exogenous environmental or maternal factors or from inborn genetic anomalies. However, our understanding of the cellular basis of IUGR or miscarriage is blocked by our ignorance about the process of normal placental development. We are cognizant that normal human placental development is dependent on differentiation of the villous cytotrophoblast culminating in intercellular fusion into the expanding syncytiotrophoblast on the placental surface. Syncytialization involves several processes, particularly cessation of cellular proliferation, redistribution of plasma membrane phospholipids to form a phosphatidylserine (PS)-rich exofacial surface, expression and insertion of fusion proteins into the plasma membrane, and rearrangement of actin cytoskeletal elements. Our preliminary data suggest that several apoptosis-related proteins, particularly caspases 3, 8, and 14, may be critical participants in trophoblast differentiation. The aim of this application is to investigate the role of these caspases in villous cytotrophoblast differentiation. We will use both primary villous cytotrophoblast cultures and a BeWo choriocarcinoma model. Using peptide inhibitors and gene silencing, we will determine the role of caspases 3, 8, and 14 in individual components of the syncytialization process (PS efflux, G1 arrest, cytoskeletal rearrangement, fusion protein expression, hCG production). Additional studies will evaluate the role of signal transduction through NFκB. The ultimate goal of this investigation is to identify the critical components controlling the mechanism of villous cytotrophoblast differentiation. Unexplained IUGR and miscarriage are common complications that lead to death of a child or to a severely compromised newborn requiring extensive care in newborn intensive care units. With the information obtained through this research, we can begin to investigate the placental defects that may explain IUGR or miscarriage, and thereby design diagnostic tests or interventions to decrease the risk of these complications.

常见的妊娠并发症，如宫内生长受限（IUGR）和流产，与胎盘发育异常密切相关，可能是由外源环境或母体因素或先天遗传异常引起的。 IUGR 或流产是由于我们对这一问题的无知而阻碍的 我们认识到，正常的人胎盘发育依赖于绒毛细胞滋养层的分化，最终在胎盘表面上融合成扩张的合体滋养层，特别是细胞增殖的停止、质膜的重新分布。磷脂形成富含磷脂酰丝氨酸（PS）的外表面，融合蛋白的表达和插入我们的初步数据表明，质膜和肌动蛋白细胞骨架元件的重排。 一些凋亡相关蛋白，特别是半胱天冬酶 3、8 和 14，可能是滋养层分化的关键参与者。本应用的目的是研究这些半胱天冬酶在绒毛细胞滋养层分化中的作用。我们将使用两种原代绒毛细胞滋养层培养物。和 BeWo 绒毛膜癌模型，我们将使用肽抑制剂和基因沉默来确定 caspase 3、8 和 的作用。 14 在合胞化过程的各个组成部分（PS 流出、G1 停滞、细胞骨架重排、融合蛋白表达、hCG 产生）中，其他研究将评估通过 NFκB 的信号转导作用。 根据通过这项研究获得的信息，我们确定了控制绒毛细胞滋养层分化机制的关键成分。不明原因的 IUGR 和流产是导致儿童死亡或新生儿严重受损的常见并发症。可以开始调查可能解释 IUGR 或流产的胎盘缺陷，从而设计诊断测试或干预措施以降低这些并发症的风险。