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而发生了数百万年的转变，随着宿主的适应和使用，可遗传的整合到生殖细胞的基因组中可能导致快速的进化变化。大约 8% 的人类基因组具有明显的逆转录病毒来源，少数内源性逆转录病毒 (ERV) 整合位点保留了分离的转录活性开放。阅读框架，以便可以表达各种 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。在正常人绒毛细胞滋养层分化过程中表达的 env 区域中具有开放阅读框的单拷贝 ERV 基因组我们通过 cAMP/蛋白激酶 A 依赖性确定了 ERV3 env 表达。途径，对于 ¿ 的表达至关重要-hCG 在合体滋养层中。我们的初步研究结果表明，活性位点位于 ERV3 Env 的 N 末端部分（称为 p25 区域），这是与逆转录病毒 Env 蛋白相关的独特发现，一般而言，针对 ERV3 env 的 siRNA 转染完全阻断了 ¿ -hCG。我们发表的初步数据支持这样的假设：ERV-3 env 表达通过调节 ¿ 对正常滋养层分化和植入至关重要。 -hCG 表达。该 R21 的目标是获得支持未来 RO1 必须获得的某些关键数据。ERV3 Env 对 ¿ 的作用机制。 -hCG 表达 我们将研究 ERV3 env 表达影响 ¿ 表达的途径。 -hCG。我们将确定该途径是否通过 ERV3 Env 和辅助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的 ERV3 Env 受体介导的过程：ERV3 env 表达的影响。 ¿ -hCG 启动子的激活。 -hCG 启动子可能继发于 cAMP 依赖性转录因子，或者如果 ERV3 Env 是转录因子则直接发生。 研究将评估这两个潜在过程。