Genomic Dissection of Placental Lesions in Preeclampsia
先兆子痫胎盘病变的基因组解剖
基本信息
- 批准号:10742701
- 负责人:
- 金额:$ 42.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAreaBindingBiological AssayBloodBlood VesselsCRISPR/Cas technologyCell LineClinicalClonal ExpansionCopy Number PolymorphismDNADNA Sequence AlterationDefectDevelopmentDiseaseDissectionEtiologyFetal Growth RetardationFetal healthFlow CytometryFunctional disorderGeneticGenomicsGoalsHistologicHuman Cell LineHypertensionImmuneImmune ToleranceIn VitroInjuryInvadedIschemiaKnock-inLesionMHC Class I GenesMHC binding peptideMaternal MortalityMicroscopicModelingMosaicismMutateMutationNucleotidesOrganOxidative StressPathogenesisPeptidesPerfusionPlacentaPlacentationPlayPre-EclampsiaPregnancyProliferatingProteinuriaQuantitative Reverse Transcriptase PCRReperfusion InjuryResearchRoleSingle Nucleotide PolymorphismSomatic MutationSpiral Artery of the EndometriumSyncytiotrophoblastT-Cell ReceptorTestingTissuesUmbilical Cord BloodValidationVariantVascular EndotheliumVascular remodelingVillouscytokinecytotrophoblastearly onsetfallsfetalgenome sequencinghealthy pregnancyhypoperfusionimmunocytochemistryimmunogenicimmunogenicityimprovedin vitro Modelinduced pluripotent stem cellinterestlaser capture microdissectionloss of function mutationmutantparticlesevere maternal morbiditystem cellstranscriptometrophoblasttrophoblast stem cellvascular abnormalityvascular injuryvasoconstrictionwhole genome
项目摘要
PROJECT SUMMARY
Preeclampsia (PE) affects 3-8% of pregnancies and is a leading cause of severe maternal morbidity and
mortality. PE pathogenesis involves abnormal EVT differentiation and invasion, which leads to failed remodeling
of spiral arteries, resulting in hypoperfusion of the placenta that causes oxidative stress. Developmental
abnormalities in the placenta manifest as histopathological lesions that arise from these defects and include
maternal vascular malperfusion (MVM), a constellation of gross and microscopic findings that represent
abnormal perfusion through the maternal vascular channels. Recently, widespread placental mosaicism and
frequent mutations have been characterized in normal placental tissue, suggesting that this is a common feature
of placental development arising from distinct clonal expansions. The role that these mutations play in
histopathological lesions such as MVM, placental dysfunction, maternal-fetal immune tolerance is poorly
understood. We hypothesize that somatic mutations contribute to the etiology of preeclampsia by
affecting trophoblast differentiation, proliferation and immunogenicity. We will model the functional
consequences of somatic mutations on in vitro trophoblast proliferation and differentiation by establishing
trophoblast stem cell (TSC) lines from human placenta-derived induced pluripotent stem cells (iPSC) and use
CRISPR-Cas9 to knock-in previously identified PE-associated loss-of-function mutations in each iPSC line. We
will characterize the trophoblast proliferation and differentiation potential and immunogenicity of mutated and
isogenic control iPSC-TSC lines using qRT-PCR, flow cytometry, immunocytochemistry, functional assays, and
cytokine arrays at the TSC (cytotrophoblast/CTB) stage and following differentiation into syncytiotrophoblasts
(STB) and extravillous trophoblasts (EVT). Next, we will characterize the mutational landscape of histopathologic
lesions (MVM) in placentas from severe early onset PE and without PE. We will perform whole genome
sequencing at 30X coverage and single nucleotide, copy number and structural variant calling to identify germline
(maternal and fetal) and somatic mutations within the placenta and placental lesions. We will calculate
mutational burden, predict immunogenicity and perform a clinical enrichment analysis to identify mutations
enriched in placental lesions relative to matched normal regions and in preeclampsia relative to normal, which
will identify mutations associated with PE and MVM as candidates for further functional testing. Modeling the
functional roles of placental mutations with in vitro modeling of trophoblast differentiation, proliferation and
immunogenicity will further our understanding of the cellular dynamics of placental dysfunction in preeclampsia.
项目总结
子痫前期(PE)影响3-8%的妊娠,是严重孕产妇发病率和
死亡率。PE的发病机制涉及EVT的异常分化和侵袭,从而导致重构失败
螺旋动脉受累,导致胎盘灌流不足,导致氧化应激。发展中
胎盘的异常表现为由这些缺陷引起的组织病理学损害,包括
母体血管灌注不良(MVM),一系列大体和微观表现,代表
通过母体血管通道的异常血流。最近,普遍存在的胎盘马赛克和
在正常胎盘组织中发现了频繁突变的特征,这表明这是一种常见的特征。
胎盘发育的起源于不同的克隆扩张。这些突变在其中扮演的角色
组织病理损害,如MVM,胎盘功能障碍,母婴免疫耐受性差
明白了。我们假设,体细胞突变通过以下方式在先兆子痫的病因中起作用
影响滋养层细胞分化、增殖和免疫原性。我们将对功能
建立体细胞突变对体外滋养层细胞增殖和分化的影响
人胎盘诱导多能干细胞(IPSC)的滋养层干细胞(TSC)株及其应用
CRISPR-Cas9在每个IPSC系中敲入先前发现的与PE相关的功能丧失突变。我们
将表征滋养层细胞的增殖分化潜能和免疫原性
应用qRT-PCR、流式细胞术、免疫细胞化学、功能分析和免疫组织化学等方法检测同基因对照IPSC-TSC
TSC(细胞滋养层/CTB)阶段和分化为合体滋养层细胞后的细胞因子阵列
(STB)和绒毛外滋养细胞(EVT)。接下来,我们将描述组织病理学的突变图景
重度早发胎盘和无胎盘早发胎盘的病变(MVM)。我们将进行全基因组测试
30倍覆盖率测序和单核苷酸、拷贝数和结构变异呼唤以鉴定种系
胎盘和胎盘病变内的(母体和胎儿)和体细胞突变。我们会计算出
突变负担,预测免疫原性,并执行临床浓缩分析以识别突变
相对于匹配的正常区域的胎盘病变和相对于正常的子痫前期
将确定与PE和MVM相关的突变,作为进一步功能测试的候选。为您的
胎盘突变在滋养层细胞分化、增殖和体外模拟中的功能作用
免疫原性将进一步加深我们对子痫前期胎盘功能障碍的细胞动力学的理解。
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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Kathleen Marie Fisch其他文献
Kathleen Marie Fisch的其他文献
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{{ truncateString('Kathleen Marie Fisch', 18)}}的其他基金
Pregnant Female Reproductive Tissue Mapping Center Data Analysis Core
孕妇生殖组织图谱中心数据分析核心
- 批准号:
10531090 - 财政年份:2022
- 资助金额:
$ 42.66万 - 项目类别:
Pregnant Female Reproductive Tissue Mapping Center Data Analysis Core
孕妇生殖组织图谱中心数据分析核心
- 批准号:
10701367 - 财政年份:2022
- 资助金额:
$ 42.66万 - 项目类别:
Pregnant Female Reproductive Tissue Mapping Center Data Analysis Core
孕妇生殖组织图谱中心数据分析核心
- 批准号:
10670433 - 财政年份:2022
- 资助金额:
$ 42.66万 - 项目类别:
Female Reproductive Tissue Mapping Center Data Analysis Core
女性生殖组织图谱中心数据分析核心
- 批准号:
10119156 - 财政年份:2020
- 资助金额:
$ 42.66万 - 项目类别:
Female Reproductive Tissue Mapping Center Data Analysis Core
女性生殖组织图谱中心数据分析核心
- 批准号:
10268241 - 财政年份:2020
- 资助金额:
$ 42.66万 - 项目类别:
Omics Data Generation Center (ODGC) for the Acute to Chronic Pain Signatures (A2CPS) Program
急性至慢性疼痛特征 (A2CPS) 计划的组学数据生成中心 (ODGC)
- 批准号:
10000873 - 财政年份:2019
- 资助金额:
$ 42.66万 - 项目类别:
Omics Data Generation Center (ODGC) for the Acute to Chronic Pain Signatures (A2CPS) Program
急性至慢性疼痛特征 (A2CPS) 计划的组学数据生成中心 (ODGC)
- 批准号:
10224832 - 财政年份:2019
- 资助金额:
$ 42.66万 - 项目类别:
Omics Data Generation Center (ODGC) for the Acute to Chronic Pain Signatures (A2CPS) Program
急性至慢性疼痛特征 (A2CPS) 计划的组学数据生成中心 (ODGC)
- 批准号:
10415817 - 财政年份:2019
- 资助金额:
$ 42.66万 - 项目类别:
Omics Data Generation Center (ODGC) for the Acute to Chronic Pain Signatures (A2CPS) Program
急性至慢性疼痛特征 (A2CPS) 计划的组学数据生成中心 (ODGC)
- 批准号:
10680641 - 财政年份:2019
- 资助金额:
$ 42.66万 - 项目类别:
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