Role of ADAMTS13 in Maternal Complications of Preeclampsia

ADAMTS13 在先兆子痫孕产妇并发症中的作用

• 批准号: 9119325
• 负责人: S. Ananth Karumanchi
• 金额: $ 27.98万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119325
• 关键词: ADAMTS; Acute Kidney Failure; Adhesions; Affect; Anemia; Angiogenic Factor; Biological; Biology; Blood; Blood Platelets; Blood coagulation; Brain; Chemotherapy-Oncologic Procedure; Cleaved cell; Clinical; Cohort Studies; Complement; Development; Disease; Disintegrins; Enzymes; Exhibits; Fetal Growth Retardation; Fetus; Genetic; HELLP Syndrome; Hemolysis; Hemolytic Anemia; Human; Hypertension; Injury; Kidney; Knockout Mice; Laboratories; Lead; Life; Link; Liver; Measurement; Measures; Metalloproteases; Mus; Organ; Pathogenesis; Pathology; Pathway interactions; Pilot Projects; Placental Growth Factor; Plasma; Platelet Count measurement; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Birth; Proteins; Proteinuria; Recombinants; Renal function; Risk Factors; Rodent; Role; Symptoms; Syndrome; Therapeutic; Third Pregnancy Trimester; Thrombocytopenia; Thrombosis; Toxic effect; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Viscera; Woman; Zinc; adverse outcome; fetal; inhibitor/antagonist; member; modifiable risk; mouse model; novel therapeutics; overexpression; public health relevance; von Willebrand Disease; von Willebrand Factor

 DESCRIPTION (provided by applicant): Thrombotic microangiopathies (TMAs) are a heterogeneous group of life-threatening disorders characterized by thrombocytopenia, schistocytosis, hemolytic anemia, microvascular thrombosis and end-organ damage affecting the kidney and brain. During pregnancy, TMAs may present as preeclampsia (PE), characterized by hypertension and proteinuria with glomerular endotheliosis (a form of thrombotic microangiopathy), or as part of the HELLP syndrome (Hemolysis, Elevated Liver enzymes and Low Platelet count) which is typically classified as a severe form of PE. Recent studies suggest that at least among preterm PE (<34 weeks), angiogenic imbalance as a result of excessive circulating anti-angiogenic factors plays a role in the development of PE pathology. While there a number of placental derived anti-angiogenic factors, our laboratory has characterized the role of soluble fms like tyrosine kinase 1 (sFlt1), a circulating vascular endothelial growth factor inhibitor in the pathogenesis of preeclampsia. Rodent studies suggest that excess sFlt1 is sufficient to induce the maternal syndrome of PE. Humans receiving VEGF inhibitors as part of cancer chemotherapy also get PE-like state and rarely develop full blow thrombotic microangiopathy that resembles HELLP syndrome. In this proposal, we hypothesize that deficiency of the VWF-cleaving enzyme ADAMTS13, a protein that has been linked to the genetic forms of thrombotic microangiopathies contributes to the development of severe preeclampsia and HELLP syndrome. ADAMTS13 is a zinc containing metalloprotease enzyme that cleaves von Willebrand factor (VWF), a large protein involved in blood clotting. In humans, both ADAMTS13 and VWF levels are critical determinants for the development of various TMAs. In pilot studies, ADAMTS13-/- mice overexpressing sFlt1 in the non-pregnant state developed severe hypertension, thrombocytopenia, schistocytosis, anemia and microthrombi in multiple organs. We will therefore first evaluate whether deficiency of ADAMTS13 contributes to the development of HELLP syndrome in a mouse model of PE characterized by high circulating sFlt1. We will also perform initial proof-of-concept studies to evaluate whether recombinant ADAMTS13 will rescue features of severe PE in our mouse model without overt adverse consequences to the fetus. Finally, we will measure ADAMTS13 and its target VWF during third trimester of pregnancy in blood among women with normal and PE pregnancies and will correlate alternations in these hematological factors with PE- related adverse maternal/fetal adverse outcomes (elevated liver enzymes, low platelets, very preterm delivery or fetal growth restriction). These studies may have broader relevance to other forms of TMAs.

 描述(申请人提供)：血栓性微血管病(TMA)是一组不同类型的危及生命的疾病，其特征是血小板减少、血吸虫病、溶血性贫血、微血管血栓形成和影响肾脏和大脑的终末器官损害。在妊娠期，TMA可能表现为先兆子痫(PE)，特征是高血压和蛋白尿伴肾小球内皮细胞增生症(一种血栓性微血管病变)，或者是HELLP综合征的一部分(溶血、肝酶升高和血小板计数降低)，后者通常被归类为严重的PE形式。最近的研究表明，至少在早产儿PE(34周)中，由于循环中过量的抗血管生成因子导致的血管生成失衡在PE的病理发展中起着一定的作用。虽然有许多胎盘衍生的抗血管生成因子，但我们的实验室已经确定了可溶性FMS，如酪氨酸激酶1(SFlt1)，一种循环中的血管内皮生长因子抑制物在子痫前期发病机制中的作用。啮齿动物研究表明，过量的sFlt1足以诱发PE的母体综合征。作为癌症化疗的一部分，接受血管内皮生长因子抑制剂治疗的患者也会出现类似PE的状态，很少会出现类似HELLP综合征的全面血栓性微血管病变。在这项建议中，我们假设VWF裂解酶ADAMTS13的缺乏，这种蛋白与血栓性微血管病变的遗传形式有关，导致严重的子痫前期和HELLP综合征的发生。ADAMTS13是一种含锌的金属蛋白酶，可分解von Willebrand因子(VWF)，VWF是一种参与凝血的大型蛋白质。在人类中，ADAMTS13和VWF水平都是各种TMA发生的关键决定因素。在初步研究中，在非怀孕状态下过度表达sFlt1的ADAMTS13/-小鼠出现了严重的高血压、血小板减少、血吸虫病、贫血和多个器官的微血栓。因此，我们将首先评估ADAMTS13缺乏是否有助于以高循环sFlt1为特征的PE小鼠模型的HELLP综合征的发生。我们还将进行初步的概念验证研究，以评估重组ADAMTS13是否将挽救我们的小鼠模型中严重PE的特征，而不会对胎儿产生明显的不良后果。最后，我们将在正常妊娠和PE妊娠的妊娠晚期测量ADAMTS13及其目标VWF，并将这些血液学因素的变化与PE相关的不良母婴不良结局(肝酶升高、血小板降低、极早产或胎儿生长受限)相关联。这些研究可能对其他形式的TMA具有更广泛的相关性。