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，例如宫内生长限制（IUGR）和流产，与Plopeta异常发育密切相关。缺陷的放置可能是由极端的环境或遗物因素或先天遗传异常引起的。但是，我们对IUGR或流产的细胞基础的理解被我们对 我们认识到，正常的人类位置发育取决于在细胞间融合中最终融合到斑点表面上膨胀的宁生细胞细胞的分化。合成化涉及几个过程，尤其是细胞增殖，质膜磷脂的重新分布，形成磷脂酰丝氨酸（PS） - 富含外叶面表面，融合蛋白的表达和插入质膜膜中的表达和插入，并插入质膜和重排中的肌动蛋白细胞骨骼元素。我们的初步数据暗示 几种与凋亡相关的蛋白，尤其是胱天蛋白酶3、8和14的蛋白质可能是滋养细胞分化的关键参与者。该应用的目的是研究这些胱天蛋白酶在绒毛细胞营养细胞分化中的作用。我们将使用原发性绒毛细胞增生质细胞培养物和绒毛膜绒毛膜模型。使用肽抑制剂和基因沉默，我们将确定胱天蛋白酶3、8和14在同步过程的各个组件中的作用（PS外排，G1停滞，细胞骨架重排，融合蛋白表达，HCG产生）。其他研究将评估通过NFκB信号转导的作用。这项调查的最终目标是 确定控制绒毛细胞质细胞分化机制的关键成分。无法解释的IUGR和流产是常见的并发症，导致儿童死亡或严重受损的新生儿，需要在新生儿重症监护病房中进行广泛的护理。通过这项研究获得的信息，我们可以开始研究可能解释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。