ERV3 Control of Human Placentation

ERV3 对人类胎盘着床的控制

• 批准号: 8575770
• 负责人: NEAL STEWART ROTE
• 金额: $ 23.78万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8575770
• 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(申请人提供)：大多数脊椎动物和一些无脊椎动物的基因组在数百万年的时间里通过传染性逆转录病毒的整合而改变。生殖细胞基因组的可遗传整合可能导致了快速的进化变化，因为宿主适应和使用了有利的逆转录病毒蛋白。大约8%的人类基因组明显来源于逆转录病毒。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，从而可以表达各种Gag(基质和衣壳)、Poll(聚合酶和其他酶)和env(包膜)蛋白。发育中的胎盘是少数在生理条件下表达ERV蛋白的器官之一。ERV3是一个单拷贝的ERV基因组，在env区有一个开放阅读框，在正常的人绒毛细胞滋养层细胞分化过程中表达。我们通过cAMP/蛋白激酶A依赖的途径确定erv3 env的表达对于合体滋养层细胞中hCG的表达是必不可少的。初步研究结果表明，活性部位位于 Erv3Env的N-末端部分(指p25区域)，这是一个与逆转录病毒Env蛋白相关的独特发现。靶向erv3 env的siRNA完全阻断？-hCG的诱导。我们已发表的和初步的数据支持这样一个假设，即ERV-3env的表达对正常滋养细胞的分化和着床是必不可少的，这是通过调节hCG的表达来实现的。此R21的目标是获得支持未来RO1必须获得的某些关键数据。目的1.erv3env对人绒毛膜促性腺激素(HCG)表达的作用机制。我们将研究erv3 env表达影响？-hCG表达的途径。我们将确定这一途径是否通过erv3Env与辅助因子或辅助分子之间的细胞内复合体的形成而被激活。我们还将研究另一种分泌的erv3env受体介导的过程。目的2：人绒毛膜促性腺激素启动子erv3 env表达的影响。-hCG启动子的激活可能发生在cAMP依赖的转录因子之后，或者直接发生在erv3Env是转录因子的情况下。研究将对这两个潜在的过程进行评估。