Endogenous Retroviruses and Placental Morphogenesis

描述（由申请方提供）：哺乳动物成功妊娠需要孕体（胚胎/胎儿和相关的胚外胎盘膜）的生长和分化。胎盘是从母体向胚胎/胎儿输送营养和气体的关键。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，以提供基础知识，用于开发合理的治疗方法，用于预防和临床治疗妊娠丢失和涉及胎盘发育不全，发育不良和功能障碍的疾病。这项研究计划特别关注内源性逆转录病毒（ERVs）在孕体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在人胎盘中表达，并且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。在本研究项目中，实验旨在确定内源性β-逆转录病毒在绵羊胚胎发育和胎盘形态发生的围着床期的生物学作用。绵羊携带内源性β逆转录病毒（称为内源性绵羊肺腺瘤病毒或enJSRV），其在子宫内膜上皮和胎盘中特异性和高度表达。透明质酸酶2（HYAL 2）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enJSRVs Env在绵羊体内孕体中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。核心假设是enJSRVEnv和HYAL 2调节单核滋养层细胞增殖、双核细胞分化和多核合胞体的形成。这些实验利用新的想法和研究方法来确定enJSRVs和Hyal 2细胞受体在滋养层生长和分化中的生物学作用。成功完成的实验，预计将阐明调控机制控制的基本过程中必不可少的建立和维持怀孕的内源性逆转录病毒调节。

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.