ERV3 Control of Human Placentation

ERV3 对人类胎盘着床的控制

• 批准号: 8712530
• 负责人: NEAL STEWART ROTE
• 金额: $ 19.26万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-05 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712530
• 关键词: Active Sites; Adult; Affect; Biological Process; Capsid; Capsid Proteins; Cell membrane; Cleaved cell; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Deletion Mutation; Elements; Endogenous Retroviruses; Enzymes; Funding; Future; Gagging; Genetic; Genome; Germ Cells; Goals; HERVs; Human; Human Chorionic Gonadotropin; Human Genome; Immunosuppressive Agents; Invertebrates; Knock-out; Length; Long Terminal Repeats; Marsupialia; Mediating; Membrane; Membrane Fusion; Messenger RNA; Modeling; Modification; Mutation; N-terminal; Open Reading Frames; Organ; Pathway interactions; Peptides; Physiological; Placenta; Placentation; Polymerase; Positioning Attribute; Process; Protein Kinase; Protein Region; Proteins; Publications; Publishing; Regulation; Reporting; Research; Research Personnel; Residual state; Retroviridae; Retrovirus Proteins; Role; Sampling; Secondary to; Site; Small Interfering RNA; Surface; Syncytiotrophoblast; Terminator Codon; Transfection; Translating; Transmembrane Domain; Vertebrates; Villous; Virion; cohort; cytotrophoblast; env Gene Products; gag Gene Products; hormone regulation; implantation; pol Gene Products; promoter; public health relevance; receptor; syncytin; transcription factor; trophoblast

DESCRIPTION (provided by applicant): The genome of most vertebrates and some invertebrates has been transformed over millions of years by the integration of infectious retroviruses. Inheritable integrations into the genome of germ cells may have led to rapid evolutionary changes as the host accommodated and used advantageous retroviral proteins. Approximately 8% of the human genome is of apparent retroviral origin. A small number of endogenous retrovirus (ERV) integration sites retained isolated transcriptionally active open reading frames so that a variety of gag (matrix and capsid), pol (polymerase and other enzymes), and env (envelope) proteins may be expressed. The developing placenta is one of few organs that express ERV proteins under physiologic conditions. ERV3 is a single copy ERV genome with an open reading frame in the env region that is expressed during normal human villous cytotrophoblast differentiation. We determined that ERV3 env expression, through a cAMP/protein kinase A dependent pathway, is essential for expression of ¿-hCG in the syncytiotrophoblast. Results of our preliminary studies indicate that the active site is located in the N-terminal portion of ERV3 Env (referred to the p25 region), a unique finding related to retroviral Env proteins in general. Transfection of siRNA targeted to ERV3 env completely blocks induction of ¿-hCG. Our published and preliminary data support a hypothesis that ERV-3 env expression is essential for normal trophoblast differentiation and implantation through regulation of ¿ -hCG expression. The goal of this R21 is to obtain certain critical data must be obtained in support of a future RO1. AIM 1. Mechanism of action of ERV3 Env on ¿-hCG expression. We will investigate the pathway through which ERV3 env expression affects expression of ¿-hCG. We will determine whether this pathway is activated through intracellular complex formation between ERV3 Env and co-factors or accessory molecules. We will also investigate an alternative secreted ERV3 Env-receptor mediated process. AIM 2: Effects of ERV3 env expression of the ¿ -hCG promoter. Activation of the ¿-hCG promoter may occur secondary to cAMP-dependent transcription factors or directly if ERV3 Env is a transcription factor. Studies will evaluate both potential processes.

描述（由申请人提供）：大多数脊椎动物和一些无脊椎动物的基因组已经通过感染性逆转录病毒的整合在数百万年内发生了变化。遗传整合到生殖细胞基因组中可能导致宿主适应和使用有利的逆转录病毒蛋白质时的快速进化变化。大约8%的人类基因组是明显的逆转录病毒起源。少数内源性逆转录病毒（ERV）整合位点保留了独立的转录活性开放阅读框，因此可以表达多种gag（基质和衣壳）、pol（聚合酶和其他酶）和env（包膜）蛋白。发育中的胎盘是在生理条件下表达ERV蛋白的少数器官之一。ERV 3是在env区具有开放阅读框的单拷贝ERV基因组，其在正常人绒毛细胞滋养层分化期间表达。我们确定ERV 3 env的表达，通过cAMP/蛋白激酶A依赖的途径，是在合体滋养层中表达<$-hCG所必需的。我们的初步研究结果表明，活性位点位于 ERV 3 Env的N-末端部分（称为p25区域），这是一个与一般逆转录病毒Env蛋白相关的独特发现。靶向ERV 3 env的siRNA的转染完全阻断了？-hCG的诱导。我们已发表的初步数据支持这样的假设：ERV-3 env表达通过调节？-hCG表达对于正常滋养层分化和着床至关重要。此R21的目标是获得某些关键数据，这些数据必须获得以支持未来的RO 1。AIM 1. ERV 3 Env对hCG表达的作用机制。我们将研究ERV 3 env表达影响<$-hCG表达的途径。我们将确定该途径是否通过ERV 3 Env与辅因子或辅助分子之间的细胞内复合物形成而被激活。我们还将研究另一种分泌型ERV 3 Env受体介导的过程。目的2：ERV 3 env表达的影响-hCG启动子。<$-hCG启动子的激活可能继发于cAMP依赖性转录因子，或者如果ERV 3 Env是转录因子则直接激活。研究将评估这两个潜在的过程。