FUNCTIONS OF PREGNANCY SPECIFIC GLYCOPROTEINS

描述(申请人提供)：人类妊娠特异性糖蛋白(PSGs)是一种蛋白质家族，由胎盘分泌到母体血液循环中，从植入时到足月。抗体中和PSGs会导致灵长类动物和啮齿类动物的自发流产，这表明它们在妊娠成功中起着关键作用。PSG样蛋白只在有绒毛膜胎盘的物种中发现，在这种物种中，母亲的血液与胎儿组织直接接触。我们之前已经证明，人类和小鼠PSG家族的一些成员可以诱导抗炎细胞因子的分泌，这是已知的对妊娠成功至关重要的因素。这些细胞因子包括IL-10、前列腺素E2和转化生长因子1，它们可以防止白细胞的渗透和子宫内白细胞的杀伤激活。虽然我们发现到目前为止研究的小鼠和人类PSG具有相同的活性，但它们使用的受体不同。我们确定小鼠Psg17和Psg19与Tetraspanin CD9结合，但小鼠PSG家族其他15个成员的活性和受体用途仍有待研究。人类PSG不使用CD9作为其受体，人类PSG家族所有11个成员的受体的身份尚不清楚。我们的长期目标是确定PSG在怀孕期间的作用和作用机制。我们应用的中心假设是PSGs在巨噬细胞上有一个特定的受体，并且该受体与小鼠和人PSGs N-末端区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起着关键作用。最终，这有助于建立与妊娠成功相适应的免疫环境，因为巨噬细胞在蜕膜中构成一个稳定的群体，负责在整个怀孕期间产生局部先天免疫。这项拟议研究背后的理论基础是需要为活体研究建立有效的动物模型，以更好地了解这些糖蛋白通过胎盘表达来调节免疫反应的机制。此外，通过克隆人类PSG受体，我们将能够确定人类和小鼠系统之间的相似之处。为了实现这一应用的目标，我们将追求三个具体目标：(1)克隆人PSG的受体。(2)确定小鼠PSG家族的代表性成员是否使用CD9作为其受体，并分析人和小鼠PSG N结构域中的溶剂暴露环对其功能的重要性。(3)确定CD9相互作用蛋白的参与，并确定CD9中对PSG 17的应答所需的结构域。我们期望所获得的结果最终将有助于开发新的治疗策略，用于治疗反复妊娠松弛的妇女和Th-1引起的自身免疫性疾病。

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.