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（由申请人提供）：血栓性微血管病 (TMA) 是一组异质性危及生命的疾病，其特征为血小板减少、片状细胞增多、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伤。先兆子痫（PE），以高血压和蛋白尿为特征，伴有肾小球内皮增生（血栓形成的一种形式）微血管病），或作为 HELLP 综合征（溶血、肝酶升高和血小板计数低）的一部分，该综合征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，血管生成失衡是一种常见的症状。过度循环的抗血管生成因子在 PE 病理学的发展中发挥作用，虽然存在许多胎盘源性抗血管生成因子，但我们的实验室已经表征了酪氨酸激酶等可溶性 fms 的作用。 1 (sFlt1) 是一种循环血管内皮生长因子抑制剂，在先兆子痫的发病机制中发挥作用。 啮齿类动物研究表明，过量的 sFlt1 足以诱发 PE 母体综合征，接受 VEGF 抑制剂作为癌症化疗一部分的人类也会出现 PE 样状态。很少会出现类似于 HELLP 综合征的全面血栓性微血管病。在这项提案中，我们与 VWF 裂解酶 ADAMTS13 的缺乏进行了斗争，该酶与 VWF 裂解酶 ADAMTS13 相关。血栓性微血管病的遗传形式会导致严重先兆子痫和 HELLP 综合征的发生 ADAMTS13 是一种含锌金属蛋白酶，可裂解冯维勒布兰德因子 (VWF)，这是一种参与人类血液凝固的大蛋白。在初步研究中，ADAMTS13-/- 小鼠在 sFlt1 中过度表达。因此，我们将首先在以高循环 sFlt1 为特征的 PE 小鼠模型中评估 ADAMTS13 的缺乏是否会导致 HELLP 综合征的发生。进行初步概念验证研究，以评估重组 ADAMTS13 是否能够挽救我们的小鼠模型中严重 PE 的特征，而不会对小鼠模型产生明显的不良后果最后，我们将在正常妊娠和 PE 妊娠妇女的妊娠晚期血液中测量 ADAMTS13 及其目标 VWF，并将这些血液学因素的变化与 PE 相关的母体/胎儿不良结局（肝酶升高、低水平）关联起来。血小板、严重早产或胎儿生长受限）。这些研究可能与其他形式的 TMA 具有更广泛的相关性。