Not all members of the pregnancy-specific glycoprotein family are created equal

项目总结 胎盘分泌的因子作为免疫调节所需的媒介的重要性 适应具有血绒毛胎盘的物种中不同基因的母亲和胎儿(啮齿动物，非 人类灵长类动物和人类)是公认的。母亲和母亲之间对资源的利益冲突 在哺乳动物怀孕期间，后代被假设为推动一场进化的军备竞赛。这可能会导致 基因复制事件导致蛋白质家族的增加，如妊娠特异性糖蛋白(PSG) 家族，这在胎盘中并不少见。单核细胞(M0)和巨噬细胞(Mϕ)失调 与妊娠病理有关，如先兆子痫(PE)和早产以及这些先天细胞 免疫系统主要负责肿瘤坏死因子的释放，这是一种强有力的促炎细胞因子。而当 肿瘤坏死因子反应有助于早孕蜕膜滋养层细胞的侵袭和分娩， 肿瘤坏死因子也与不良妊娠结局有关。因此，在时间和空间上的调节。 炎症是妊娠成功所必需的复杂而必要的过程。人类PSG，一个 胎盘滋养层细胞在整个妊娠期间分泌到母体循环的十种蛋白质家族，是 由3个或4个Ig样结构域组成。虽然PSG已经通过复制从单个基因扩展，但它仍然 尚不清楚这些基因在扩增后是否获得了不同的功能。此外，由于序列的原因， 区分人类PSG家族每个成员的相似性和特异性抗体是不可用的，但 在信使核糖核酸水平上的研究表明，它们在怀孕期间表达的水平和时间不同。 PSG1在体内外均有抗炎活性，且浓度较低 在被诊断为PE的非裔美国女性中，这一比例高于正常。相比之下，有报道称PSG9基因上调 在体育课。最近我们还观察到用PS9治疗M0和Mϕ，而不用PS1、PS4和PSG7治疗 导致肿瘤坏死因子分泌增加。基于这些观察，我们提出了一个创新的假设 在人类PSG中，PSG9通过与M0和Mϕ中的特定细胞受体结合而具有独特的功能 导致这些细胞产生促炎细胞因子。我们建议用以下方法来检验我们的假设 以下具体目标：(1)确定PSG9是否在所有人类PSG中具有独一无二的能力 在单核/巨噬细胞中诱导促炎细胞因子并确定PSG9中参与这一过程的结构域 活动。(2)确定PSG9在单核/巨噬细胞中的细胞受体与其诱导能力相关 这些细胞的肿瘤坏死因子。PSG9抗炎活性的验证及其受体和受体的鉴定 潜在的靶向将使诊断工具和新的治疗干预措施的开发成为可能 一些病理性妊娠的病因学。对存活的后代和母亲的长期好处可能 具有巨大的经济和社会后果。

PROJECT SUMMARY The importance of factors secreted by the placenta as mediators of the immunological adjustments needed to accommodate the genetically different mother and fetus in species with hemochorial placentation (rodents, non- human primates and humans) is well recognized. Conflicting interests for resources between mother and offspring are hypothesized to drive an evolutionary arms race during mammalian pregnancy. This can result in gene duplication events giving raise to protein families, such as the pregnancy-specific glycoprotein (PSG) family, which are not uncommon in the placenta. Monocyte (M0) and macrophage (Mϕ) dysregulation are implicated in pregnancy pathologies such as preeclampsia (PE) and preterm birth and these cells of the innate immune system are primarily responsible for the release of TNF, a potent pro-inflammatory cytokine. While the TNF response contributes to trophoblast invasion in the early decidua and to parturition, increased levels of TNF are also associated with adverse pregnancy outcomes. Therefore, the temporal and spatial regulation of inflammation represents a complex and essential process required for pregnancy success. Human PSGs, a family of ten proteins secreted by placental trophoblasts to the maternal circulation throughout pregnancy, are composed of 3 or 4 Ig-like domains. While PSGs have expanded from a single gene by duplication, it remains unknown whether after expansion, these genes have acquired different functions. Moreover, due to sequence similarities, specific antibodies that differentiate each member of the human PSG family are not available, but studies at the mRNA level have indicated that they are expressed at different levels and times during gestation. PSG1 has anti-inflammatory activities in vitro and in vivo and the concentration of PSG1 was found to be lower than normal in African American women diagnosed with PE. In contrast, PSG9 was reported to be upregulated in PE. Recently, we also observed that treatment of M0 and Mϕ with PSG9 but not with PSG1, PSG4 and PSG7 resulted in increased TNFsecretion. Based on these observations, we propose an innovative hypothesis that PSG9 has a unique function among human PSGs via binding to a specific cellular receptor in M0 and Mϕ resulting in the production of pro-inflammatory cytokines by these cells. We propose to test our hypothesis with the following Specific Aims: (1) Determine whether PSG9 is unique among all the human PSGs in its ability to induce pro-inflammatory cytokines in monocyte/macrophages and define the domain in PSG9 involved in this activity. (2) Identify the cellular receptor of PSG9 in monocytes/macrophages associated with its ability to induce TNF in these cells. Validation of the pro-inflammatory activity of PSG9 and identification of its receptor and its potential targeting will enable the development of diagnostic tools and novel therapeutic interventions to address the etiology of some pathological pregnancies. The long-term benefit to surviving offspring and the mother could have enormous economic and social consequences.