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.

抑制（PE）是一种特定于孕妇的综合征，已在 PE的发病机理包括完成（C）级联激活。循环中的C激活副产品 女性怀孕的升高，PE女性在PE妇女中得到了显着升高。胎盘 与正常性女性相比，PE的C活化副产物的沉积也显着升高。 胎儿/plapeta的半作用性质诱导物物c级联激活。了解原因 C激活与妊娠高血压之间的影响关系，必须深入了解 机械途径将胎盘激活与怀孕高血压和胎儿生长限制联系起来 针对潜在治疗发现的这些途径的观点。一种可能的机制是C 激活可能促进全身性抗血管生成和促炎环境，母体血管功能障碍， 高血压和肾脏病理变化。此外，C的激活可能会导致占地纤维蛋白沉积 与凝结系统的串扰，促进胎儿生长限制。在此应用程序中，我们将确定 使用新颖的机制将C激活与妊娠高血压和胎儿生长限制联系起来 补体基于激活的鼠标模型。这种转基因鼠标模型使我们能够在 一种诱导，条件和胎盘特定方式，并研究其对各种母校系统的影响。 特定目的1。评估PLACETA特定C激活是否促进了全身性抗血管生成 以及促炎环境，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）和促炎的全身水平提高 分子（TNF-α，IL-6和IL-8），弛豫减少和收缩反应增加（血管 母体外周动脉，高血压，子宫螺旋动脉有缺陷（SA）的功能障碍） 通过C3A-C3AR/C5A-C5AR，STAT3和STAT3和 ERK路径。此外，使用特定抑制剂CR2-Crry抑制C激活可以改善这些C 诱导的变化。特定目的2。测试C激活诱导斑点纤维蛋白的假设 通过其与凝结系统串扰的沉积，促进胎儿生长限制。 假设：C激活通过减少由于胎儿血液供应而促进胎儿生长的限制 通过组织因子（TF）和von Willebrand的破坏，胎盘绿绿纤维蛋白沉积 因子（vwf）体内平衡。 C直接通过C5A-C5AR信号激活，并间接通过 促炎细胞因子IL6，IL8和TNF-α诱导TF，纤溶酶原激活剂的上调 抑制剂1和VWF由内皮细胞，并在肝脏中下调ADAMTS-13。