Role of ADAMTS13 in Maternal Complications of Preeclampsia
ADAMTS13 在先兆子痫孕产妇并发症中的作用
基本信息
- 批准号:9119325
- 负责人:
- 金额:$ 27.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:ADAMTSAcute Kidney FailureAdhesionsAffectAnemiaAngiogenic FactorBiologicalBiologyBloodBlood PlateletsBlood coagulationBrainChemotherapy-Oncologic ProcedureCleaved cellClinicalCohort StudiesComplementDevelopmentDiseaseDisintegrinsEnzymesExhibitsFetal Growth RetardationFetusGeneticHELLP SyndromeHemolysisHemolytic AnemiaHumanHypertensionInjuryKidneyKnockout MiceLaboratoriesLeadLifeLinkLiverMeasurementMeasuresMetalloproteasesMusOrganPathogenesisPathologyPathway interactionsPilot ProjectsPlacental Growth FactorPlasmaPlatelet Count measurementPlayPre-EclampsiaPregnancyPregnancy ComplicationsPremature BirthProteinsProteinuriaRecombinantsRenal functionRisk FactorsRodentRoleSymptomsSyndromeTherapeuticThird Pregnancy TrimesterThrombocytopeniaThrombosisToxic effectVascular Endothelial Growth Factor Receptor-1Vascular Endothelial Growth FactorsVisceraWomanZincadverse outcomefetalinhibitor/antagonistmembermodifiable riskmouse modelnovel therapeuticsoverexpressionpublic health relevancevon Willebrand Diseasevon Willebrand Factor
项目摘要
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(由申请方提供):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症、裂红细胞增多症、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。在妊娠期间,TMA可能表现为先兆子痫(PE),其特征在于高血压和蛋白尿伴肾小球内皮增生(血栓性微血管病的一种形式),或作为HELLP综合征(溶血、肝酶升高和血小板计数低)的一部分,其通常被归类为重度PE。最近的研究表明,至少在早产儿PE(<34周)中,由于过度循环抗血管生成因子导致的血管生成失衡在PE病理学的发展中起作用。虽然有许多胎盘源性抗血管生成因子,我们的实验室已经表征了可溶性fms如酪氨酸激酶1(sFlt 1),循环血管内皮生长因子抑制剂在先兆子痫发病机制中的作用。啮齿动物研究表明,过量的sFlt 1足以诱导PE的母体综合征。接受VEGF抑制剂作为癌症化疗的一部分的人也会出现PE样状态,很少发生类似HELLP综合征的完全性血栓性微血管病。在这个提议中,我们假设VWF裂解酶ADAMTS 13(一种与血栓性微血管病的遗传形式有关的蛋白质)的缺乏有助于重度先兆子痫和HELLP综合征的发展。ADAMTS 13是一种含锌的金属蛋白酶,可切割血管性血友病因子(VWF),一种参与血液凝固的大蛋白质。在人类中,ADAMTS 13和VWF水平是各种TMA发展的关键决定因素。在初步研究中,在非妊娠状态下过表达sFlt 1的ADAMTS 13-/-小鼠在多个器官中出现重度高血压、血小板减少症、裂红细胞症、贫血和微血栓。因此,我们将首先评估ADAMTS 13缺陷是否有助于在以高循环sFlt 1为特征的PE小鼠模型中发展HELLP综合征。我们还将进行初步的概念验证研究,以评估重组ADAMTS 13是否会在我们的小鼠模型中挽救重度PE的特征,而不会对胎儿产生明显的不良后果。最后,我们将测量正常和PE妊娠妇女妊娠晚期血液中的ADAMTS 13及其靶VWF,并将这些血液学因素的变化与PE相关的不良母体/胎儿不良结局(肝酶升高、血小板减少、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。
项目成果
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S. Ananth Karumanchi其他文献
ニコチンアミドは妊娠高血圧に有効である
烟酰胺对妊娠高血压有效
- DOI:
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2012 - 期刊:
- 影响因子:0
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高橋信行;Feng Li;Charles Jennette;S. Ananth Karumanchi;Oliver Smithies;高橋信行;高橋信行 - 通讯作者:
高橋信行
993 Plasma sFlt-1/PlGF ratio in mom and severe adverse neonatal outcomes in non-preeclamptic patients
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10.1016/j.ajog.2023.11.1020 - 发表时间:
2024-01-01 - 期刊:
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Jimmy Espinoza;Vinicius Calsavara;Elizabeth Lemoine;Sarah Kilpatrick;Ravi Thadhani;S. Ananth Karumanchi - 通讯作者:
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ニコチンアミドは妊娠高血圧腎症に有効である
烟酰胺对先兆子痫有效
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- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
高橋信行;Feng Li;Charles Jennette;Oliver Smithies;S. Ananth Karumanchi - 通讯作者:
S. Ananth Karumanchi
1059 Maternal Angiogenic Imbalance & Placental Sexual Dimorphism
- DOI:
10.1016/j.ajog.2023.11.1086 - 发表时间:
2024-01-01 - 期刊:
- 影响因子:
- 作者:
Elizabeth Lemoine;Vinicius Calsavara;Ravi Thadhani;Sarah Kilpatrick;S. Ananth Karumanchi;Kim Boggess - 通讯作者:
Kim Boggess
Lipid-delivery system could treat life-threatening pregnancy complication
脂质递送系统可治疗危及生命的妊娠并发症
- DOI:
10.1038/d41586-024-03853-w - 发表时间:
2024-12-11 - 期刊:
- 影响因子:48.500
- 作者:
Ravi Thadhani;S. Ananth Karumanchi - 通讯作者:
S. Ananth Karumanchi
S. Ananth Karumanchi的其他文献
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{{ truncateString('S. Ananth Karumanchi', 18)}}的其他基金
Placental Organoids for Modeling and Treating Preeclampsia
用于建模和治疗先兆子痫的胎盘类器官
- 批准号:
10464766 - 财政年份:2022
- 资助金额:
$ 27.98万 - 项目类别:
2012 Endothelial Cell Phenotypes in Health & Disease GRC/GRS
2012 健康中的内皮细胞表型
- 批准号:
8390350 - 财政年份:2012
- 资助金额:
$ 27.98万 - 项目类别:
Redefining Vitamin D Deficiency: The Role of Bioavailable Vitamin D
重新定义维生素 D 缺乏症:生物可利用维生素 D 的作用
- 批准号:
9015435 - 财政年份:2012
- 资助金额:
$ 27.98万 - 项目类别:
Angiogenesis-related gene products in preeclampsia
先兆子痫中血管生成相关的基因产物
- 批准号:
7010387 - 财政年份:2005
- 资助金额:
$ 27.98万 - 项目类别:
Angiogenesis-related gene products in preeclampsia
先兆子痫中血管生成相关的基因产物
- 批准号:
7365256 - 财政年份:2005
- 资助金额:
$ 27.98万 - 项目类别:
Angiogenesis-related gene products in preeclampsia
先兆子痫中血管生成相关的基因产物
- 批准号:
7174642 - 财政年份:2005
- 资助金额:
$ 27.98万 - 项目类别:
Angiogenesis-related gene products in preeclampsia
先兆子痫中血管生成相关的基因产物
- 批准号:
6870361 - 财政年份:2005
- 资助金额:
$ 27.98万 - 项目类别:
Role of VEGF in Glomerular Endothelial Health & Diseases
VEGF 在肾小球内皮健康中的作用
- 批准号:
7239601 - 财政年份:2004
- 资助金额:
$ 27.98万 - 项目类别:
Role of VEGF in Glomerular Endothelial Health & Diseases
VEGF 在肾小球内皮健康中的作用
- 批准号:
6822487 - 财政年份:2004
- 资助金额:
$ 27.98万 - 项目类别:
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