Angiogenesis-related gene products in preeclampsia
先兆子痫中血管生成相关的基因产物
基本信息
- 批准号:7365256
- 负责人:
- 金额:$ 20.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-02-01 至 2009-01-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAngiogenic FactorAngiogenic ProteinsAnimal ModelBindingBiological AssayBlood CirculationBlood Coagulation DisordersBlood VesselsCell Surface ReceptorsClinicalCytoplasmic TailDataDevelopmentDiseaseEdemaEquilibriumEtiologyEventFunctional disorderGene ExpressionGene Expression RegulationHeterozygoteHypertensionHypoxiaImmunohistochemistryIn VitroIschemiaKidney FailureKnockout MiceLeadLesionMessenger RNAModelingMolecularMorbidity - disease ratePathogenesisPatient currently pregnantPatientsPlacentaPlacental Growth FactorPlacentationPlayPre-EclampsiaPregnancyPregnant WomenPreventionProductionProperdinProteinsProteinuriaRNA SplicingRattusReceptor Protein-Tyrosine KinasesReportingResearch PersonnelRodentRoleSerumSymptomsTestingTherapeuticTimeTranscriptional ActivationUp-RegulationVariantVascular Endothelial Growth Factor ReceptorVascular Endothelial Growth Factor Receptor-1Vascular Endothelial Growth FactorsWeekWomanangiogenesisantiangiogenesis therapycytotrophoblastfallsfetalglomerular filtrationin vivoin vivo Bioassayinsightmortalitynormotensivenovelnovel therapeuticspodocytepreventprogramsresearch studyresponse
项目摘要
DESCRIPTION (provided by applicant): Preeclampsia (PE) is a disease, which affects 5-7% of all pregnancies and is characterized by severe hypertension, proteinuria and edema. Endothelial dysfunction plays an important role in the pathogenesis of this disorder; however, the etiology and mechanisms are still unknown. We recently found that placentas from preeclamptic patients produce an excess of a naturally occurring anti-angiogenic protein, sFIt-1 (soluble fms-like tyrosine kinase-1), resulting in increased serum levels in patients with PE as compared to normotensive pregnant women. Fit-1 is one of the tyrosine kinase receptors for vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). sFIt-1, a secreted splice variant of Fit-1 (lacking the transmembrane and cytoplasmic domains) potently antagonizes VEGF and PIGF, by preventing their binding to the cell-surface receptor. Moreover, we have found that the ratio of anti-angiogenic (sFIt-1) to pro-angiogenic (VEGF + PIGF) proteins in the maternal bloodstream at the time of delivery is substantially elevated in preeclamptic women as compared with control pregnant women. In vitro, preeclamptic serum but not normal pregnant serum induces endothelial dysfunction due to excess sFIt-1, which can be rescued by exogenous VEGF and PIGF. Finally, we have preliminary data that administration of exogenous sFIt-1 to pregnant rats induces hypertension, heavy proteinuria and glomerular endotheliosis, the classic lesion of PE. We therefore hypothesize that alteration in the angiogenic balance due to excess sFLt-1 results in the development of PE. This proposal aims to clarify the role of sFIt-1 and altered angiogenic balance in the pathogenesis of PE. We will first characterize our sFIt-1 induced animal model for PE and will test several therapeutic compounds in an attempt to find new treatment options for patients with PE. We will then elucidate the mechanisms of systemic vascular dysfunction and placental cytotrophoblast dysfunction induced by excess sFIt-1 and altered angiogenic balance using both in vitro and in vivo experiments. Finally, we will focus on studying the transcriptional and post-transcriptional regulatory mechanisms of sFIt-1 production by placental cytotrophoblasts. These focused studies will form the beginnings of a framework for understanding the role of angiogenesis-related gene products in pathogenesis of PE and for exploring novel avenues for the treatment of PE.
描述(由申请人提供):先兆子痫(PE)是一种影响所有妊娠的 5-7% 的疾病,其特征是严重高血压、蛋白尿和水肿。内皮功能障碍在该疾病的发病机制中起着重要作用。然而,其病因和机制仍不清楚。我们最近发现先兆子痫患者的胎盘产生过量的天然存在的抗血管生成蛋白 sFIt-1(可溶性 fms 样酪氨酸激酶-1),导致 PE 患者的血清水平与血压正常的孕妇相比升高。 Fit-1 是血管内皮生长因子 (VEGF) 和胎盘生长因子 (PIGF) 的酪氨酸激酶受体之一。 sFIt-1 是 Fit-1 的一种分泌性剪接变体(缺乏跨膜和细胞质结构域),通过阻止 VEGF 和 PIGF 与细胞表面受体结合,有效拮抗 VEGF 和 PIGF。此外,我们发现,与对照孕妇相比,先兆子痫女性在分娩时母体血液中抗血管生成(sFIt-1)与促血管生成(VEGF + PIGF)蛋白的比率显着升高。在体外,先兆子痫血清而非正常妊娠血清会因过量的 sFIt-1 引起内皮功能障碍,而外源性 VEGF 和 PIGF 可以挽救这种功能障碍。最后,我们有初步数据表明,给怀孕大鼠注射外源性sFIt-1会诱发高血压、大量蛋白尿和肾小球内皮增生,这是PE的典型病变。因此,我们假设 sFLt-1 过量导致血管生成平衡的改变导致 PE 的发生。该提案旨在阐明 sFIt-1 和改变的血管生成平衡在 PE 发病机制中的作用。我们将首先表征 sFIt-1 诱导的 PE 动物模型,并将测试几种治疗化合物,试图为 PE 患者找到新的治疗选择。然后,我们将通过体外和体内实验阐明过量 sFIt-1 和血管生成平衡改变引起的全身血管功能障碍和胎盘细胞滋养层功能障碍的机制。最后,我们将重点研究胎盘细胞滋养层产生sFIt-1的转录和转录后调控机制。这些重点研究将为了解血管生成相关基因产物在肺栓塞发病机制中的作用和探索治疗肺栓塞的新途径奠定基础。
项目成果
期刊论文数量(1)
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:
$ 20.54万 - 项目类别:
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 - 财政年份:2016
- 资助金额:
$ 20.54万 - 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:
$ 20.54万 - 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:
$ 20.54万 - 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:
$ 20.54万 - 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:
$ 20.54万 - 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:
$ 20.54万 - 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:
$ 20.54万 - 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:
$ 20.54万 - 项目类别:
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