FUNCTIONS OF PREGNANCY SPECIFIC GLYCOPROTEINS

描述（由申请方提供）：人妊娠特异性糖蛋白（Psgs）是从着床至足月期间由胎盘分泌到母体循环中的蛋白质家族。抗体中和Psgs导致灵长类和啮齿类动物的自然流产，表明它们在妊娠成功中的关键作用。psg样蛋白只存在于血绒膜胎盘形成的物种中，其中母体血液与胎儿组织直接接触。我们以前已经表明，人类和小鼠Psg家族的一些成员诱导抗炎细胞因子的分泌，这是已知的怀孕成功是重要的。这些细胞因子包括IL-10、前列腺素E2和TGF-β 1，防止白细胞的浸润和子宫内驻留细胞的杀伤活化。虽然我们发现到目前为止研究的小鼠和人类Psgs具有相同的活性，但它们使用不同的受体。我们确定，鼠Psg 17和Psg 19结合四跨膜蛋白CD 9，但活性和受体的使用的其他15个成员的鼠Psg家族仍有待研究。人Psg不使用CD 9作为其受体，并且人Psg家族的所有11个成员的受体的身份是未知的。我们的长期目标是确定Psgs在妊娠期间的作用和作用机制。本申请的中心假设是Psgs在巨噬细胞上具有特异性受体，并且受体与鼠和人Psgs的N-末端结构域内的溶剂暴露环的相互作用在触发导致抗炎细胞因子分泌的信号级联中具有关键作用。最终，这有助于建立与妊娠成功相容的免疫环境，因为巨噬细胞在蜕膜中构成稳定的群体，负责在整个妊娠期间产生局部先天免疫。提出的研究背后的基本原理是基于需要生成用于体内研究的有效动物模型，以更好地理解这些糖蛋白（具有独家胎盘表达）调节免疫应答的机制。此外，通过克隆人Psgs的受体，我们将能够确定人类和小鼠系统之间的相似之处。为了实现本申请的目的，我们将追求三个具体目标：（1）克隆人Psgs的受体。(2)确定鼠Psg家族的代表性成员是否使用CD 9作为其受体，并分析人和鼠Psg N结构域中溶剂暴露环对其功能的重要性。(3)确定CD 9相互作用蛋白的参与，并确定对Psg 17的反应所需的CD 9结构域。我们期望所获得的结果将最终有助于开发新的治疗策略，用于患有复发性妊娠丢失的妇女和Th-1驱动的自身免疫性疾病的管理。

DESCRIPTION (provided by applicant): 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.