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: 10521835
• 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/10521835
• 关键词: ADAMTS; Ablation; Allogenic; Amniotic Fluid; Angiogenesis Inhibitors; Arteries; Biological; Blood Circulation; C3AR1 gene; CD46 Antigen; Cell membrane; Cells; Cessation of life; Coagulation Process; Complement; Complement 3a; Complement 3d Receptors; Complement 5a; Complement Activation; Complement Factor H; Complement Membrane Attack Complex; Complement Receptor; Data; Deposition; Disease; Embryo; Endothelial Cells; Epidemiology; Fetal Growth Retardation; Fetus; Fibrin; Fibrinogen; Functional disorder; Future; Genetic Polymorphism; Genetic Predisposition to Disease; High Prevalence; Homeostasis; Human; Hypertension; IL6 gene; IL8 gene; Injury; Interleukin-6; Investigation; Kidney; Link; Liquid substance; Liver; Lytic; 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; Play; Pre-Eclampsia; Pregnancy; Process; Proteins; Regulation; Relaxation; Reporting; Rodent; Role; STAT3 gene; 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; base; complement pathway; complement system; cytokine; fetal; fetal blood; gene complementation; 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，有几种假定的机制与此相关。 PE 的发病机制包括循环中补体 (C) 级联激活的副产物。 女性怀孕时会升高，胎盘女性中会进一步显着升高。 与血压正常的女性相比，PE 患者 C 激活副产物的沉积也显着升高。 胎儿/胎盘的半同种异体性质诱导母体 C 级联激活 了解原因和- C 激活与妊娠期高血压之间的影响关系，有必要深入了解 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 针对这些途径进行潜在治疗发现的观点是，C。 激活可能促进全身抗血管生成和促炎环境、母体血管功能障碍、 此外，C 激活可能诱发胎盘纤维蛋白沉积。 与凝血系统的串扰，促进胎儿生长受限。在此应用中，我们将确定。 使用新型机制将 C 激活与妊娠高血压和胎儿生长受限联系起来 基于激活的小鼠模型。这种转基因小鼠模型允许补体下调 Crry 的表达。 一种诱导性、条件性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学 通过 C3a-C3aR 和/或 C5a-C5aR、STAT3 和 ERK 途径 假设：C 激活期间。 妊娠促进抗血管生成（sFLT1、sEng）和促炎物质的全身水平增加 分子（TNF-α、IL-6 和 IL-8），减少舒张反应并增加收缩反应（血管 母亲外周动脉功能障碍、高血压、子宫螺旋动脉（SA）缺陷 通过 C3a-C3aR/C5a-C5aR、STAT3 和 此外，使用特异性抑制剂 CR2-Crry 抑制 C 激活可改善这些 C 信号。 具体目标 2. 检验 C 激活诱导胎盘纤维蛋白的假设。 通过与凝血系统的串扰而沉积，促进胎儿生长受限。 假设：C 激活通过减少胎儿血液供应来促进胎儿生长受限 通过破坏组织因子 (TF) 和血管性血友病导致胎盘绒毛周围纤维蛋白沉积 C 因子 (vWF) 稳态的激活直接通过 C5a-C5aR 信号传导或间接通过 促炎细胞因子 IL6、IL8 和 TNF-α 诱导 TF、纤溶酶原激活剂上调 内皮细胞抑制抑制剂 1 和 vWF，并下调肝脏中的 ADAMTS-13。