Wednesday, May 8, 2024
5/8/2024
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 (M¿) 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 M¿ 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 M¿ 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.
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