Endogenous Retroviruses and Placental Morphogenesis

内源性逆转录病毒和胎盘形态发生

• 批准号: 8299715
• 负责人: THOMAS E SPENCER
• 金额: $ 22.09万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-05 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299715
• 关键词: Abbreviations; Accounting; Animals; Antisense Oligonucleotides; Betaretrovirus; Biological; Biology; Cell Differentiation process; Cell Proliferation; Cell fusion; Cells; Chorionic Gonadotropin; Clinical; Clinical Treatment; Conceptus; Development; Diagnosis; Differentiation and Growth; Disease; Dysplasia; Endogenous Retroviruses; Endometrial; Environment; Epithelium; Ethics; Euchromatin; Eukaryota; Event; Evolution; Fetal Growth Retardation; Functional disorder; Gases; Genes; Genetic; Genome; Giant Cells; Glycoproteins; Goals; Green Fluorescent Proteins; Growth; HERVs; Health; Human; Human Genome; Hyaluronidase; In Vitro; Infertility; Inherited; Knowledge; Long Terminal Repeats; MAP Kinase Gene; Mammals; Membrane; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mononuclear; Morphogenesis; Mothers; Nature; Nutrient; Open Reading Frames; Ovine pulmonary adenocarcinoma virus; Pathway interactions; Phosphatidylinositols; Phosphotransferases; Placenta; Placental Lactogen; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Maintenance; Pregnancy loss; Prevention therapy; Process; Publishing; Regulator Genes; Reproductive Biology; Research; Research Personnel; Research Project Grants; Research Proposals; Resources; Retroviridae; Retrovirology; Role; Sheep; Signal Pathway; Testing; Transmembrane Domain; Uterus; Virus; base; cell growth; cell type; design; embryo/fetus; env Gene Products; env Genes; gain of function; human FRAP1 protein; implantation; improved; in utero; in vivo; innovation; insight; loss of function; mTOR protein; multidisciplinary; novel; placental membrane; prevent; programs; receptor; reproductive; research study; syncytin; tau interferon; theories; trophoblast

DESCRIPTION (provided by applicant): The growth and differentiation of the conceptus (embryo/fetus and associated extraembryonic placental membranes) is required in mammals for successful pregnancy. The placenta is essential for transfer of nutrients and gases to the embryo/fetus from the mother. Our long-term goal is to understand the cellular and molecular mechanisms of conceptus development and placental morphogenesis in order to provide fundamental knowledge that will be used to develop rational therapies for the prevention and clinical treatment of pregnancy loss and diseases involving placental dysgenesis, dysplasia, and dysfunction. This research proposal specifically focuses on the biological roles of endogenous retroviruses (ERVs) in conceptus development and placental morphogenesis. ERVs account for about 8% of the genome of every animal species. A number of ERVs are expressed in the human placenta and are associated with placental differentiation and pregnancy diseases such as preeclampsia. However, studies to determine the role(s) of ERVs in humans are not feasible for obvious ethical reasons. In this research project, experiments are designed to determine the biological role(s) of endogenous betaretoviruses during the peri-implantation period of conceptus development and placental morphogenesis in sheep. Sheep harbor endogenous betaretroviruses (termed endogenous Jaagsiekte Sheep Retroviruses or enJSRVs) that are specifically and highly expressed in the uterine endometrial epithelia and placenta. Hyaluronidase 2 (HYAL2), a cellular receptor for JSRV and enJSRV Env, is expressed only by the trophoblast giant binucleate cells and multinucleated syncytia of the placenta. Inhibition of enJSRVs Env expression in the sheep conceptus in vivo retards trophoblast growth, inhibits trophoblast giant binucleate cell differentiation, and compromises early pregnancy. The central hypothesis is that enJSRVs Env and HYAL2 regulate mononuclear trophoblast cell proliferation, differentiation of binucleate cells, and formation of multinucleated syncytia. The experiments utilize novel ideas and research approaches to determine the biological role of enJSRVs and the Hyal2 cellular receptor in trophoblast growth and differentiation. Successful completion of the experiments is expected to elucidate regulatory mechanisms controlling fundamental processes essential for the establishment and maintenance of pregnancy that are regulated by endogenous retroviruses.

描述（由申请人提供）：哺乳动物成功怀孕需要孕体（胚胎/胎儿和相关的胚胎外胎盘膜）的生长和分化。胎盘对于将营养物质和气体从母体转移到胚胎/胎儿至关重要。我们的长期目标是了解孕体发育和胎盘形态发生的细胞和分子机制，以便提供基础知识，用于开发合理的疗法来预防和临床治疗流产以及涉及胎盘发育不良、发育不良、和功能障碍。该研究计划特别关注内源性逆转录病毒（ERV）在概念发育和胎盘形态发生中的生物学作用。 ERV 约占每个动物物种基因组的 8%。许多 ERV 在人类胎盘中表达，并与胎盘分化和妊娠疾病（如先兆子痫）相关。然而，由于明显的伦理原因，确定 ERV 在人类中的作用的研究是不可行的。在该研究项目中，实验旨在确定内源性β-轮状病毒在绵羊胚胎发育和胎盘形态发生的植入周围时期的生物学作用。羊体内含有内源性β逆转录病毒（称为内源性Jaagsiekte羊逆转录病毒或enJSRV），它们在子宫内膜上皮和胎盘中特异性且高度表达。透明质酸酶 2 (HYAL2) 是 JSRV 和 enJSRV Env 的细胞受体，仅由胎盘的滋养层巨双核细胞和多核合胞体表达。抑制绵羊受孕体内 enJSRV Env 的表达会延缓滋养层生长，抑制滋养层巨双核细胞分化，并损害早期妊娠。中心假设是 enJSRV Env 和 HYAL2 调节单核滋养层细胞增殖、双核细胞分化以及多核合胞体的形成。这些实验利用新颖的想法和研究方法来确定 enJSRV 和 Hyal2 细胞受体在滋养层生长和分化中的生物学作用。实验的成功完成预计将阐明控制受内源性逆转录病毒调节的妊娠建立和维持所必需的基本过程的调节机制。

项目成果

Coevolution of endogenous betaretroviruses of sheep and their host.

• DOI: 10.1007/s00018-008-8500-9
• 发表时间: 2008-11
• 期刊: CELLULAR AND MOLECULAR LIFE SCIENCES
• 影响因子: 8
• 作者: Arnaud, F.;Varela, M.;Spencer, T. E.;Palmarini, M.
• 通讯作者: Palmarini, M.

Endogenous retroviruses in trophoblast differentiation and placental development.

• DOI: 10.1111/j.1600-0897.2010.00860.x
• 发表时间: 2010-10
• 期刊: American journal of reproductive immunology (New York, N.Y. : 1989)
• 作者: Black SG;Arnaud F;Palmarini M;Spencer TE
• 通讯作者: Spencer TE

"Ménage à Trois": the evolutionary interplay between JSRV, enJSRVs and domestic sheep.

• DOI: 10.3390/v6124926
• 发表时间: 2014-12-09
• 期刊: Viruses
• 作者: Armezzani A;Varela M;Spencer TE;Palmarini M;Arnaud F
• 通讯作者: Arnaud F

Application of next generation sequencing in mammalian embryogenomics: lessons learned from endogenous betaretroviruses of sheep.

• DOI: 10.1016/j.anireprosci.2012.08.016
• 发表时间: 2012-09
• 期刊: ANIMAL REPRODUCTION SCIENCE
• 影响因子: 2.2
• 作者: Spencer, Thomas E.;Palmarini, Massimo
• 通讯作者: Palmarini, Massimo

Revealing the history of sheep domestication using retrovirus integrations.

• DOI: 10.1126/science.1170587
• 发表时间: 2009-04-24
• 期刊: Science (New York, N.Y.)
• 作者: Chessa B;Pereira F;Arnaud F;Amorim A;Goyache F;Mainland I;Kao RR;Pemberton JM;Beraldi D;Stear MJ;Alberti A;Pittau M;Iannuzzi L;Banabazi MH;Kazwala RR;Zhang YP;Arranz JJ;Ali BA;Wang Z;Uzun M;Dione MM;Olsaker I;Holm LE;Saarma U;Ahmad S;Marzanov N;Eythorsdottir E;Holland MJ;Ajmone-Marsan P;Bruford MW;Kantanen J;Spencer TE;Palmarini M
• 通讯作者: Palmarini M