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

项目摘要 胎盘分泌的因子作为免疫调节介质的重要性 在具有血绒膜胎座形成的物种中适应遗传上不同的母亲和胎儿（啮齿动物，非 人类灵长类动物和人类）是公认的。在母亲和母亲之间争夺资源， 后代被假设在哺乳动物怀孕期间推动进化军备竞赛。这可能导致 基因重复事件导致蛋白质家族的产生，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（M β）失调是 与妊娠病理学如先兆子痫（PE）和早产有关，这些先天性巨噬细胞 免疫系统主要负责释放TNF α，一种有效的促炎细胞因子。而 TNF α反应有助于滋养层细胞在早期蜕膜的侵入和分娩，增加水平的TNF α， TNF α也与不良妊娠结局相关。因此， 炎症是妊娠成功所需的一个复杂而重要的过程。人类PSG，a 在整个妊娠期间，胎盘滋养层细胞分泌到母体循环的十种蛋白质家族， 由3或4个Ig样结构域组成。虽然PSG通过复制从单个基因扩展，但它仍然存在。 不知道这些基因在扩增后是否获得了不同的功能。此外，由于序列 相似之处，区分人PSG家族每个成员的特异性抗体不可用，但 mRNA水平的研究表明，它们在妊娠期间以不同的水平和时间表达。 PSG1在体外和体内均具有抗炎活性，且浓度较低 非裔美国女性PE的发病率比正常人高。相比之下，据报道，PSG 9被上调， 在体育课上。最近，我们还观察到用PSG 9治疗M0和M4，而不是用PSG 1，PSG 4和PSG 7 导致TNF α分泌增加。基于这些观察，我们提出了一个创新的假设， PSG 9通过与M0和M2中的特异性细胞受体结合而在人PSG中具有独特的功能 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： 以下具体目的：（1）确定PSG 9在所有人PSG中是否是唯一的， 诱导单核细胞/巨噬细胞中的促炎细胞因子，并定义参与此过程的PSG 9结构域 活动(2)鉴定单核细胞/巨噬细胞中PSG 9的细胞受体，其与其诱导 这些细胞中的TNF α。PSG9的促炎活性的验证及其受体的鉴定和其对炎症反应的抑制。 潜在的靶向将使诊断工具和新的治疗干预措施的发展，以解决 某些病理性妊娠的病因学对于存活下来的后代和母亲的长期利益 产生了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.