Endogenous Retroviruses and Placental Morphogenesis

描述（由申请人提供）：在哺乳动物中，成功怀孕需要母体（胚胎/胎儿和相关的胚胎外胎盘膜）的生长和分化。胎盘对于从母体向胚胎/胎儿输送营养和气体至关重要。我们的长期目标是了解胚胎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，以预防和临床治疗妊娠丢失和涉及胎盘发育不良、发育不良和功能障碍的疾病。本研究计划特别关注内源性逆转录病毒（ERVs）在胚胎发育和胎盘形态发生中的生物学作用。erv约占每种动物基因组的8%。许多erv在人胎盘中表达，并与胎盘分化和妊娠疾病（如先兆子痫）有关。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病毒在绵羊妊娠期发育和胎盘形态发生中的生物学作用。绵羊携带内源性β -逆转录病毒（内源性Jaagsiekte绵羊逆转录病毒或enjsrv），在子宫内膜上皮和胎盘中特异性和高表达。透明质酸酶2 （HYAL2）是JSRV和enJSRV Env的细胞受体，仅在胎盘的滋养细胞巨大双核细胞和多核合胞体中表达。在绵羊体内，enJSRVs Env表达的抑制会延缓滋养层细胞的生长，抑制滋养层巨双核细胞的分化，影响早期妊娠。核心假设是enJSRVs Env和HYAL2调控单核滋养细胞增殖、双核细胞分化和多核合胞体的形成。本实验利用新颖的思路和研究方法来确定enjsrv和Hyal2细胞受体在滋养细胞生长和分化中的生物学作用。实验的成功完成有望阐明内源性逆转录病毒对建立和维持妊娠至关重要的基本过程的调控机制。

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.