Placental Organoids for Modeling and Treating Preeclampsia
用于建模和治疗先兆子痫的胎盘类器官
基本信息
- 批准号:10464766
- 负责人:
- 金额:$ 4.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-22 至 2022-12-17
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAbnormal placentationActivities of Daily LivingAddressAngiogenic ProteinsBindingBlood CirculationBlood VesselsCardiovascular systemCell Culture SystemCell LineCellsCellular biologyCerebral PalsyCessation of lifeChromosome 13ClinicalDataDefectDevelopmentDevelopmental ProcessDiscipline of obstetricsDiseaseDrug ScreeningEclampsiaEmbryonic DevelopmentEndothelial Growth Factors ReceptorEpithelialEtiologyEventExhibitsFLT1 geneFetusFibroblastsFirst Pregnancy TrimesterGenesGeneticGoalsGreater sac of peritoneumHELLP SyndromeHumanHypertensionHypoxiaImmunocompromised HostImpairmentImplantIschemiaKidney FailureLTK geneLaboratoriesLeadLengthMaternal complicationMediatingMembraneMethodsModelingMonoclonal AntibodiesMothersMusNeonatal MortalityNervous System TraumaNude MiceOrganOrganoidsPatau&aposs syndromePathogenesisPathologicPathway interactionsPharmaceutical PreparationsPhenotypePhysiologyPlacentaPlacentationPlant RootsPopulationPre-EclampsiaPregnancyPremature BirthPrimatesProtein IsoformsProteinuriaProtocols documentationRapid screeningRegenerative MedicineReproducibilityResearch PersonnelRiskRodentSeizuresSignal TransductionSigns and SymptomsSmall for Gestational Age InfantSpecimenStrokeStructureSyncytiotrophoblastSyndromeTestingTimeTissuesUterusVascular Endothelial Growth Factor Receptor-1Vascular Endothelial Growth FactorsVillousWomanbiomarker developmentcell typecytotrophoblastearly onsetendothelial dysfunctionepidemiology studyexperimental studyfetalfunctional disabilityhuman modelimprovedin vivo evaluationinduced pluripotent stem cellinfancyneonatal morbiditynew therapeutic targetnonhuman primatenovelnovel therapeuticsprecision medicinepregnancy disorderreceptorself-renewalstem cell populationstem cellstherapeutic candidatetherapeutic evaluationthree dimensional cell culturetrophoblast
项目摘要
While the underlying etiology of preeclampsia (a hypertensive disorder of pregnancy)
is not known, the disease starts with shallow placentation and placental ischemia which in
turn releases excess of anti-angiogenic proteins such as soluble fms-like tyrosine kinase 1
(sFLT1) in the mother's bloodstream that is responsible for the systemic maternal endothelial
dysfunction. Self-renewing 3D epithelial organoids that closely resemble the structure and
physiology of the original organ have been successfully developed into various tissue
types using human induced pluripotent stem cells (hiPSCs). However, organoids of the
human placental trophoblasts using hiPSCs are yet to be generated. Our goal of this
proposal is to generate trophoblast organoids from disease-specific hiPSCs to study
preeclampsia pathogenesis and to screen for drugs as potential treatment targets. We
will generate a new model of trophoblast organoid using hiPSCs, replicating the early
stage of gestation from normal and preeclamptic pregnancies, a time in development that
has – until now – has been mostly inaccessible to researchers. In aim 1, we will optimize
trophoblast organoid protocols in our laboratory using hiPSCs derived trophoblast
differentiation method from donor fibroblasts and will confirm that these organoids
phenotypically and functionally behave like first trimester villous tissue. We will then test the
hypothesis that the functional capacity of trophoblast organoids derived from hiPSCs obtained
from early-onset preeclampsia will be impaired when compared to trophoblast organoids
derived from non-hypertensive controls. In aim 2, we will model maternal syndrome of
preeclampsia in nude mice with factors made by human placenta. To model human
preeclampsia, we will generate trophoblast organoids using hiPSCs derived from placental
fibroblasts from women carrying a fetus with trisomy 13, a disorder characterized by 10-fold
excess risk of preeclampsia due to extra copy of sFLT1 gene from chromosome 13. We will
then test in vivo efficacy of monoclonal antibodies that target the unique C-terminus of human
sFLT1-i14 (the isoform that is primate-specific) for enhanced clearance of sFLT1 from
systemic circulation. Due to the organoid's ready access and ability to replicate the early
stages of development from well-characterized cells, the trophoblast organoid model
promises to significantly improve our understanding of preeclampsia and provides rapid
screening methods for testing potential drugs and furthering precision medicine methods
in obstetrics.
虽然先兆子痫(一种妊娠期高血压疾病)的潜在病因
尚不清楚,这种疾病始于浅胎盘和胎盘缺血,
turn会释放过量的抗血管生成蛋白,如可溶性fms样酪氨酸激酶1
(sFLT 1)在母亲的血液,负责全身母体内皮细胞
功能障碍自我更新的3D上皮类器官与结构非常相似,
原始器官的生理机能已经成功地发育成各种组织
使用人类诱导多能干细胞(hiPSC)的类型。然而,
使用hiPSC的人胎盘滋养层细胞还有待产生。我们的目标是
一项提案是从疾病特异性hiPSC中产生滋养层类器官,以研究
子痫前期发病机制和筛选药物作为潜在的治疗目标。我们
将使用hiPSC产生一种新的滋养层类器官模型,
正常妊娠和先兆子痫妊娠的妊娠阶段,
到目前为止,研究人员还无法接触到。在目标1中,我们将优化
在我们的实验室中使用hiPSC衍生的滋养层细胞的滋养层类器官方案
从供体成纤维细胞分化的方法,并将确认这些类器官,
在表型和功能上表现得像妊娠早期绒毛组织。然后我们将测试
假设从hiPSC获得的滋养层类器官的功能能力
与滋养层类器官相比,
来自非高血压对照。在目标2中,我们将模拟
用人胎盘制备的因子对裸鼠进行子痫前期实验。来模拟人类
在先兆子痫中,我们将使用来自胎盘的hiPSC产生滋养层类器官。
来自携带13三体胎儿的妇女的成纤维细胞,13三体是一种特征为10倍染色体缺失的疾病,
由于13号染色体sFLT 1基因的额外拷贝而导致先兆子痫的过度风险。我们将
然后测试靶向人免疫球蛋白的独特C-末端的单克隆抗体的体内功效,
sFLT 1-i14(灵长类特异性同种型),用于增强sFLT 1从
体循环由于类器官容易进入并能够复制早期的
发育阶段从良好表征的细胞,滋养层类器官模型
有望显著提高我们对先兆子痫的理解,并提供快速的
用于测试潜在药物的筛选方法和进一步的精确医学方法
在产科。
项目成果
期刊论文数量(0)
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会议论文数量(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
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:
$ 4.9万 - 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:
$ 4.9万 - 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:
$ 4.9万 - 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:
$ 4.9万 - 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:
$ 4.9万 - 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:
$ 4.9万 - 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:
$ 4.9万 - 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:
$ 4.9万 - 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:
$ 4.9万 - 项目类别:
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