Pregnancy specific glycoprotein 1 activates transforming growth factor beta

描述（由申请人提供）：妊娠构成了一个独特的免疫学悖论。为了成功怀孕，表达父亲同种抗原的胎儿需要避免被母亲免疫细胞排斥。此外，母亲的免疫系统虽然对胎儿具有耐受性，但必须具有对抗感染的功能。在母胎界面和全身存在几种机制，其调节妊娠母亲的免疫状态。这些包括胎盘滋养层细胞分泌的产物，如妊娠特异性糖蛋白（PSG）。我们的建议集中在PSG在怀孕期间发挥免疫调节作用的机制。我们发现在我们实验室中产生的不同形式的重组PSG 1与抗炎细胞因子转化生长因子1（TGF-β 1）结合。这一观察结果扩展到天然PSG 1，从孕妇血清中纯化。PSG 1是否只是TGF-β 1的载体，或者它可以改变其作用仍有待确定。我们推测，PSG 1结合到潜在的TGF-β 1的结果在激活这个重要的细胞因子，除了其抗炎功能，调节许多重要的过程中，包括滋养层细胞的侵袭，内皮细胞功能，和细胞外基质沉积在怀孕期间。在PSG可以用作治疗剂之前，更好地理解PSG和TGF-β之间的关系是必要的。低于正常循环水平的PSG存在于具有不同妊娠病理学的妇女（例如小于胎龄胎儿）的妊娠血清中。最近，我们描述了除了其免疫调节功能，PSG 1是促血管生成。PSG 1与多配体聚糖中的肝素和硫酸软骨素结合，这种相互作用导致内皮细胞形成毛细血管样结构。与多配体蛋白聚糖或TGF-β相互作用的结构域和结构域内的氨基酸尚未鉴定，并且该信息是设计具有期望效果的基于PSG的治疗干预所需的。TGF-β的活化是这种多能细胞因子功能的限速步骤。虽然TGF-β的重要性在怀孕期间得到了很好的认识，但其在大多数组织中的激活却知之甚少，包括母胎界面。该项目将定义PSG 1的作用机制，并解决TGF-β 1和TGF-β 2激活的可能新机制。

DESCRIPTION (provided by applicant): Pregnancy poses a unique immunological paradox. For pregnancy to succeed, the fetus, which expresses paternal alloantigens, needs to avoid rejection by maternal immune cells. In addition, the immune system of the mother, while tolerant to the fetus, has to be functional for combating infections. Several mechanisms exist at the maternal-fetal interface and systemically, which regulate the immune status of the pregnant mother. These include secreted products by the trophoblast cells of the placenta, such as pregnancy specific glycoproteins (PSGs). Our proposal centers on the mechanisms by which PSGs exert an immune regulatory role during pregnancy. We found that different form of recombinant PSG1 generated in our laboratory is bound to the anti-inflammatory cytokine transforming growth factor 1 (TGF-b1). This observation was extended to native PSG1, purified from serum of pregnant women. Whether PSG1 is just a carrier of TGF-b1 or it can modify its action remains to be determined. We hypothesize that binding of PSG1 to latent TGF-b1 results in the activation of this important cytokine, which besides its anti-inflammatory function, regulates many important processes during pregnancy including trophoblast invasion, endothelial cell function, and extracellular matrix deposition. A better understanding of the relationship between PSGs and TGF-b is necessary before PSGs can be used as a therapeutic agent. Lower than normal circulating levels of PSGs are found in pregnant serum of women with different pregnancy pathologies such as small for gestational age fetuses. Recently, we described that besides its immune regulatory function, PSG1 is pro-angiogenic. PSG1 binds to the heparin and chondroitin sulfate in syndecans and this interaction results in the formation of capillary-like structures by endothelial cells. The domains, and amino acids within a domain, which interact with syndecans or TGF-b have not been identified and this information is required for a design of a PSG-based therapy intervention with the desired effect. The activation of TGF-b is the rate limiting step in the function of this pluripotent cytokine. While the importance of TGF-b is very well recognize during pregnancy, its activation is very poorly understood in most tissues, including the maternal-fetal interface. This project will define the mechanism of action o PSG1 and address a possible novel mechanism of TGF-b1 and TGF-b2 activation.