Evaluating role of complement activation induced signaling pathways in preeclampsia pathology using a novel complement activation-based mouse model

使用基于补体激活的新型小鼠模型评估补体激活诱导的信号通路在先兆子痫病理学中的作用

• 批准号: 10644021
• 负责人: Manu Banadakoppa
• 金额: $ 40.13万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644021
• 关键词: ADAMTS; Ablation; Allogenic; Amniotic Fluid; Angiogenesis Inhibitors; Arteries; Biological; C3AR1 gene; CD46 Antigen; Cell membrane; Cessation of life; Circulation; Coagulation Process; Complement; Complement 3a; Complement 3d Receptors; Complement 5a; Complement Activation; Complement Factor H; Complement Membrane Attack Complex; Complement Receptor; Cytoprotection; Data; Deposition; Disease; Embryo; Endothelial Cells; Epidemiology; Fetal Growth Retardation; Fetal Reduction; Fetus; Fibrin; Fibrinogen; Functional disorder; Future; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; High Prevalence; Homeostasis; Human; Hypertension; IL6 gene; IL8 gene; Inflammatory; Injury; Interleukin-6; Investigation; Kidney; Link; Liquid substance; Liver; Mannose Binding Lectin; Maternal Mortality; Maternal-Fetal Exchange; Mediating; Medical; Methodology; Modeling; Molecular; Morbidity - disease rate; Mus; Nature; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peripheral; Phase; Placenta; Plasminogen Activator Inhibitor 1; Pre-Eclampsia; Pregnancy; Process; Proteins; Regulation; Relaxation; Reporting; Rodent; Role; STAT3 gene; Signal Induction; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Spiral Artery of the Endometrium; Spontaneous abortion; Syndrome; System; TNF gene; Testing; Therapeutic; Thromboplastin; Transgenic Mice; Up-Regulation; Uterus; Vascular Diseases; Vascular blood supply; Villous; Woman; Y protein; activation product; cytokine; fetal; inflammatory milieu; inhibitor; insight; mortality; mouse model; new therapeutic target; normotensive; novel; pathophysiology of preeclampsia; pregnancy hypertension; response; von Willebrand Factor

Preeclampsia (PE) is a pregnancy-specific syndrome and several putative mechanisms have been implicated in the pathogenesis of PE including complement (C) cascade activation. C activation byproducts in the circulation are elevated with pregnancy in women and they are further elevated significantly in PE women. Placental deposition of C activation byproducts is also significantly elevated in PE compared to normotensive women. The semi-allogenic nature of fetus/placenta induces maternal C cascade activation. To understand the cause-and- effect relation between C activation and pregnancy hypertension, it is essential to gain insight into the mechanistic pathways that link placental C activation to pregnancy hypertension and fetal growth restriction with the view of targeting these pathways for potential therapeutic discoveries. One possible mechanism is that C activation may promote systemic antiangiogenic and proinflammatory milieu, maternal vascular dysfunction, hypertension and renal pathological changes. Further, C activation may induce placental fibrin deposition due to crosstalk with coagulation system, promoting fetal growth restriction. In this application we will determine the mechanisms that link C activation to pregnancy hypertension and fetal growth restriction using a novel complement activation-based mouse model. This transgenic mouse model allows us to downregulate Crry in an inducible, conditional and placenta specific manner and study its effects on various maternal systems. Specific aim 1. To assess if placenta specific C activation promotes systemic antiangiogenic and proinflammatory milieu, hypertension, maternal vascular dysfunction, and renal pathology through C3a-C3aR and/or C5a-C5aR, STAT3 and ERK pathways. Hypothesis: C activation during pregnancy promotes increased systemic levels of antiangiogenic (sFLT1, sEng) and proinflammatory molecules (TNF-α, IL-6 and IL-8), reduced relaxation and increased contractile responses (vascular dysfunction) of maternal peripheral arteries, hypertension, defective uterine spiral artery (SA) remodeling, and glomerular endotheliosis (renal pathology) through C3a-C3aR/C5a-C5aR, STAT3 and ERK pathways. Further, inhibition of C activation using specific inhibitor CR2-Crry ameliorates these C induced changes. Specific aim 2. To test the hypothesis that C activation induces placental fibrin deposition through its crosstalk with coagulation system promoting fetal growth restriction. Hypothesis: C activation promotes fetal growth restriction by reducing fetal blood supply due to placental peri-villous fibrin deposition through the disruption of tissue factor (TF) and von Willebrand factor (vWF) homeostasis. C activation directly through C5a-C5aR signaling and indirectly through proinflammatory cytokines IL6, IL8 and TNF-α induces the upregulation of TF, plasminogen activator inhibitor 1 and vWF by endothelial cells and downregulates the ADAMTS-13 in liver.

先兆子痫（PE）是一种妊娠特异性综合征， PE的发病机制包括补体（C）级联激活。C循环中的活化副产物 在女性中随着妊娠而升高，并且在PE女性中进一步显著升高。胎盘 与血压正常的妇女相比，PE中C活化副产物的沉积也显著升高。的 胎儿/胎盘的半同种异体性质诱导母体C级联激活。为了了解原因， C激活与妊娠高血压的关系，有必要了解C激活与妊娠高血压的关系。 将胎盘C激活与妊娠高血压和胎儿生长受限联系起来的机制途径， 针对这些途径的潜在治疗发现的观点。一种可能的机制是C 活化可促进全身性抗血管生成和促炎环境，母体血管功能障碍， 高血压和肾脏病变。此外，C活化可诱导胎盘纤维蛋白沉积， 与凝血系统相互干扰，促进胎儿生长受限。在本应用程序中，我们将确定 使用一种新的方法将C激活与妊娠高血压和胎儿生长受限联系起来的机制 基于补体激活的小鼠模型。这种转基因小鼠模型使我们能够下调Crry， 一种诱导的，条件性的和胎盘特异性的方式，并研究其对各种母体系统的影响。 具体目标1.评估胎盘特异性C激活是否促进全身性抗血管生成 和促炎环境、高血压、母体血管功能障碍和肾脏病理 通过C3 a-C3 aR和/或C5 a-C5 aR、STAT 3和ERK途径。假设：C激活期间 妊娠促进抗血管生成（sFLT 1，sEng）和促炎症的全身水平增加 分子（TNF-α，IL-6和IL-8），减少舒张和增加收缩反应（血管 功能障碍），高血压，子宫螺旋动脉（SA）缺陷 通过C3 a-C3 aR/C5 a-C5 aR、STAT 3和 ERK通路。此外，使用特异性抑制剂CR2-Crry抑制C活化改善了这些C 诱发的变化。具体目标2。为了检验C激活诱导胎盘纤维蛋白的假设， 通过其与凝血系统的相互作用促进胎儿生长受限。 假设：C激活通过减少胎儿血液供应促进胎儿生长受限， 通过破坏组织因子（TF）和von Willebrand的胎盘绒毛周围纤维蛋白沉积 因子（vWF）稳态。C激活直接通过C5 a-C5 aR信号传导和间接通过 促炎细胞因子IL 6、IL 8和TNF-α诱导TF、纤溶酶原激活物的上调 inhibitor 1和vWF通过内皮细胞和下调肝脏中的ADAMTS-13。