Pregnancy specific glycoprotein 1 activates transforming growth factor beta

妊娠特异性糖蛋白 1 激活转化生长因子 β

基本信息

批准号：
8533727
负责人：
Gabriela S Dveksler
金额：
$ 21.16万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-21 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8533727
关键词：
Address Alloantigen Allografting Amino Acids Anti-Inflammatory Agents Anti-inflammatory Binding Biological Biological Assay Biological Availability Biological Process Blood Circulation Blood Vessels Blood capillaries Blood flow Cell Differentiation process Cell Surface Receptors Cell physiology Cell surface Cells Chondroitin Sulfates Dendritic Cells Deposition Development Endothelial Cells Ensure Environment Enzyme-Linked Immunosorbent Assay Evolution Extracellular Matrix Family Fetal Development Fetal Growth Fetal Growth Retardation Fetal Tissues Fetus Glycoproteins Growth Factor Hemochorial Placental Development Heparan Sulfate Proteoglycan Heparin Heparitin Sulfate Immune Immune response Immune system Infection Inflammation Laboratories Lead Maternal-Fetal Exchange Molecular Mothers Nutrient Pathology Placenta Placentation Play Pre-Eclampsia Pregnancy Pregnancy Complications Pregnancy Maintenance Pregnancy Outcome Pregnancy Proteins Pregnant Women Premature Labor Process Protein Family Protein Isoforms Proteins RNA Splicing Receptor Signaling Recombinants Regulation Reporter Role Serum Small for Gestational Age Infant Spontaneous abortion Structure Syncytiotrophoblast T-Lymphocyte Testing Therapeutic Agents Therapeutic Intervention Tissues Transforming Growth Factor Beta 2 Transforming Growth Factor beta Transforming Growth Factors Variant Vascular Endothelial Growth Factor A Woman angiogenesis base capillary cell type combat cytokine design fetal immune activation immune function insight macrophage member microbial mutant novel novel therapeutics pregnant public health relevance receptor response success syndecan trophoblast

项目摘要

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.

描述（由申请人提供）：怀孕带来了独特的免疫学悖论。为了使怀孕成功，表达父亲同生的胎儿需要避免孕产妇免疫细胞排斥。另外，母亲的免疫系统虽然对胎儿的耐受性，但必须用于打击感染。在母亲界面和系统上存在几种机制，这些机制调节了怀孕母亲的免疫状态。这些包括胎盘滋养细胞的分泌产物，例如妊娠特异性糖蛋白（PSG）。我们的建议集中于PSG在怀孕期间发挥免疫调节作用的机制。我们发现，我们实验室中产生的不同形式的重组PSG1与抗炎细胞因子转化生长因子1（TGF-B1）结合。该观察结果扩展到天然PSG1，从孕妇的血清纯化。 PSG1是否只是TGF-B1的载体还是可以修改其动作尚待确定。我们假设PSG1与潜在TGF-B1的结合导致这种重要的细胞因子的激活，除了其抗炎功能外，还调节了怀孕期间许多重要过程，包括滋养细胞侵袭，内皮细胞功能，内皮细胞功能和细胞外基质沉积。在将PSG用作治疗剂之前，必须更好地了解PSG和TGF-B之间的关系。在患有不同妊娠病理学的女性的怀孕血清中发现了PSG的水平低于正常循环水平，例如胎龄小的胎儿。最近，我们描述的是，除了其免疫调节功能，PSG1是促血管生成的。 PSG1与syndecans中的肝素和软骨素结合，这种相互作用导致内皮细胞形成毛细血管样结构。尚未鉴定出与Syndecans或TGF-B相互作用的域内的域和氨基酸，并且对于基于PSG的治疗干预措施的设计是必需的，具有所需效果。 TGF-B的激活是该多能细胞因子功能的速率限制步骤。尽管在怀孕期间，TGF-B的重要性非常广泛，但在大多数组织（包括母体 - 狂欢界面）中，其激活却很少了解。该项目将定义动作O PSG1的机理，并解决TGF-B1和TGF-B2激活的新型机制。