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

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.


项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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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:
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    0
  • 作者:
    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
  • DOI:
    10.1016/j.ajog.2023.11.1020
  • 发表时间:
    2024-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Jimmy Espinoza;Vinicius Calsavara;Elizabeth Lemoine;Sarah Kilpatrick;Ravi Thadhani;S. Ananth Karumanchi
  • 通讯作者:
    S. Ananth Karumanchi
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
  • DOI:
  • 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:
Placental Organoids to Model Preeclampsia
胎盘类器官模拟先兆子痫
  • 批准号:
    10594844
  • 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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Acute Kidney Failure in a Cancer ICU
癌症 ICU 中的急性肾衰竭
  • 批准号:
    7034020
  • 财政年份:
    2006
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Acute Kidney Failure in a Cancer ICU
癌症 ICU 中的急性肾衰竭
  • 批准号:
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Acute Kidney Failure in a Cancer ICU
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  • 批准号:
    7922716
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Acute kidney failure: investigation and treatment of ki dney cell injury
急性肾衰竭:肾细胞损伤的调查和治疗
  • 批准号:
    nhmrc : 901011
  • 财政年份:
    1990
  • 资助金额:
    $ 27.98万
  • 项目类别:
    NHMRC Project Grants
Acute kidney failure: new methods of investigation and treatment
急性肾衰竭:研究和治疗的新方法
  • 批准号:
    nhmrc : 891081
  • 财政年份:
    1989
  • 资助金额:
    $ 27.98万
  • 项目类别:
    NHMRC Project Grants
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