Human pregnancy specific glycoproteins (Psgs) are a family of proteins secreted by the placenta into the maternal circulation from the time of implantation until term. Neutralization of Psgs by antibodies leads to spontaneous abortions in primates and rodents, suggesting their critical role in pregnancy success. Psg-like proteins are only found in species with hemochorial placentation, in which the maternal blood is in direct contact with fetal tissues. We have previously shown that some members of the human and murine Psg family induce the secretion of anti-inflammatory cytokines, which are known to be important for pregnancy success. These cytokines include IL-10, prostaglandin E2 and TGF 1, prevent infiltration of leukocytes and killer activation of those that are resident in the uterus. While we found that the murine and human Psgs studied so far possess the same activity, they use different receptors. We determined that murine Psg17 and Psg19 bind to the tetraspanin CD9 but the activity and receptor usage of the other 15 members of the murine Psg family remains to be studied. Human Psg do not use CD9 as their receptor and the identity of the receptor for all 11 members of the human Psg family is unknown. Our long-term goal is to define the role and mechanisms of action of Psgs during pregnancy. The central hypothesis of our application is that Psgs have a specific receptor on macrophage and that the interaction of the receptor with the solvent exposed loop within the N-terminal domain of murine and human Psgs has a critical role in triggering a signaling cascade that results in the secretion of anti-inflammatory cytokines. Ultimately, this contributes to the establishment of an immune environment that is compatible with pregnancy success, as macrophages constitute a stable population in the decidua responsible for generating local innate immunity throughout pregnancy. The rationale behind the proposed research is based on the need to generate a valid animal model for in vivo studies to better understand the mechanisms by which these glycoproteins, with exclusive placental expression, modulate the immune response. In addition, by cloning the receptor for human Psgs we will be in a position to determine the parallels between the human and murine systems. To accomplish the objectives of this application we will pursue three specific aims: (1) Clone the receptor for human Psgs. (2) Determine whether representative members of the murine Psg family use CD9 as their receptor and analyze the importance of the solvent exposed loop in the N-domain of human and murine Psgs for their function. (3) Determine the involvement of CD9-interacting proteins and define the domains in CD9 required for the response to Psg 17. We expect that the results obtained will ultimately aid in the development of new therapeutic strategies for women suffering from recurrent pregnancy looses and for the management of Th-1 driven autoimmune diseases.
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