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

• 批准号: 8359204
• 负责人: Gabriela S Dveksler
• 金额: $ 18.76万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-21 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359204
• 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; receptor; response; success; syndecan; trophoblast

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. PUBLIC HEALTH RELEVANCE: Aberrant placental angiogenesis and excessive inflammation at the maternal-fetal interface can lead to adverse pregnancy outcomes including spontaneous abortion, preterm labor, preeclampsia, and intrauterine growth restriction. This project studies the mechanism of action at the molecular level of a family of placental proteins known as pregnancy specific glycoproteins, which play a role in the process of placental vascular development and regulation of the immune response. Insights gained from these studies will help to generate novel therapeutic strategies for conditions with excessive immune activation unrelated to pregnancy and for certain pregnancy complications.

描述（由申请人提供）：怀孕是一种独特的免疫悖论。为了怀孕成功，表达父亲异体抗原的胎儿需要避免母亲免疫细胞的排斥。此外，母亲的免疫系统在对胎儿有抵抗力的同时，还必须具备抵抗感染的功能。在母胎界面和系统中存在多种机制来调节孕妇的免疫状态。这些包括胎盘滋养细胞分泌的产物，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上。我们发现在我们实验室生成的不同形式的重组PSG1与抗炎细胞因子转化生长因子1 （TGF-b1）结合。这一观察结果扩展到从孕妇血清中纯化的天然PSG1。PSG1是否只是TGF-b1的载体，还是可以改变TGF-b1的作用仍有待确定。我们假设PSG1与潜伏的TGF-b1结合导致这一重要细胞因子的激活，该细胞因子除了具有抗炎功能外，还调节妊娠期间的许多重要过程，包括滋养细胞侵袭、内皮细胞功能和细胞外基质沉积。在psg用作治疗剂之前，有必要更好地了解psg与TGF-b之间的关系。不同妊娠病理如胎龄小的孕妇血清中psg含量低于正常循环水平。最近，我们发现除了其免疫调节功能外，PSG1还具有促血管生成的作用。PSG1与syndecans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syndecans或TGF-b相互作用的结构域和结构域内的氨基酸尚未被确定，这些信息对于设计具有预期效果的基于psg的治疗干预是必需的。TGF-b的激活是这种多能细胞因子功能的限速步骤。虽然TGF-b在怀孕期间的重要性得到了很好的认识，但其在大多数组织（包括母胎界面）中的激活情况却知之甚少。该项目将明确PSG1的作用机制，并解决TGF-b1和TGF-b2激活的可能新机制。