CXCL12 regulation of placental development and fetal health
CXCL12对胎盘发育和胎儿健康的调节
基本信息
- 批准号:10405420
- 负责人:
- 金额:$ 37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-17 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AMD3100Abruptio PlacentaeAdultAmniotic FluidAnimal ModelAutophagocytosisBiologicalBlood PressureCRISPR/Cas technologyCXCL12 geneCXCR4 geneCardiovascular DiseasesCell ProliferationCell SurvivalCellsComprehensionDangerousnessDataDevelopmentDissectionEndometrialEnvironmentEtiologyEventFetal GrowthFetal Growth RetardationFetal healthFoundationsFunctional disorderFundingGenerationsGrowthGrowth FactorHealthHumanHypertensionImmuneImpairmentIn VitroInflammatoryInsulin ResistanceKDR geneKnowledgeMaternal-Fetal ExchangeMeasuresMediatingMethodsModelingMolecularMorbidity - disease rateNeonatal MortalityNon-Insulin-Dependent Diabetes MellitusObesityOutcomePGF genePathogenesisPathologicPathologyPerfusionPharmacological TreatmentPhenotypePlacentaPlacental BiologyPlacental InsufficiencyPlacentationPlant RootsPlasmaPlayPositioning AttributePre-EclampsiaPregnancyPregnancy ComplicationsProcessProductionProductivityProteomePublicationsPublishingRegulationResearchRoleSignal TransductionSolidSourceStimulation of Cell ProliferationStrokeTestingTimeUnited States National Institutes of HealthUterusVascularizationcell motilitychemokinecytokinefetalhigh riskimplantationimprovedin vivo Modelinhibitorinnovationinsightmigrationmortalitynatural Blastocyst Implantationneonatal morbiditynovel therapeuticsoffspringpotential biomarkerreceptorreceptor expressionrecruitresponseskillsstillbirthsuccesstrophoblast
项目摘要
Project Summary/Abstract
Impaired placental function leads to dangerous pregnancy complications such as preeclampsia, intrauterine
growth restriction, placental abruption, and stillbirth. Placental dysfunction is the leading cause of maternal,
fetal, and neonatal morbidity and mortality worldwide and predisposes offspring to higher risks of developing
cardiovascular disease, type 2 diabetes, insulin resistance, obesity, hypertension, and stroke during
adulthood. To improve human health, it is imperative to elucidate the mechanisms causing impaired placental
development. The chemokine, CXCL12 (L12) regulates several processes central to the development of the
placenta (placentation) such as stimulating cell proliferation and migration, vascularization, immune cell
recruitment and cytokine production through direct actions on fetal trophoblast and maternal endometrial and
immune cells. These essential functions are elicited via L12 activating its two receptors, CXCR4 (R4) and/or
CXCR7 (R7); however, the contributions of R4 compared to R7 during placentation remain unclear, denoting a
substantial gap in knowledge. Our group and others demonstrated L12-mediated signaling is strongly
implicated in placental dysfunction and specifically preeclampsia etiology. Defining L12-induced actions
through its two receptors may reveal underlying mechanisms causing placental dysfunction. We developed an
innovative animal model to study L12-dependent signaling at the fetal (trophoblast)-maternal (endometrial)
interface by delivering treatments directly into the uterus. Our published and preliminary data demonstrate
disrupting L12-mediated signaling during the small window of embryo implantation diminishes placental
vascularization, induces autophagy, and creates an excessive inflammatory placental environment later in
gestation. Notably, several observed outcomes mirror those of placental dysfunction, suggesting an imbalance
in L12/R4/R7 signaling may be causative. Preliminary data indicate transitory suppression of L12/R4 signaling
induces lasting placental insufficiency with preeclampsia markers VEGF receptor-1 (sFLT-1) and placental
growth factor (PlGF) remaining elevated months later, at midgestation. Whether excessive R7 activation
contributes to these findings when R4 is suppressed remains uncertain. Our data underscore the importance
of L12 during placentation and provide strong evidence that altering L12-mediated signaling induces enduring
placental effects manifesting later in gestation. Nevertheless, we lack a clear understanding of how L12,
excreted by fetal trophoblast cells, signals through R4 and R7 on trophoblast and maternal cells. This SC1 will
test the overall hypothesize that L12 induces distinct biological responses through R4 versus R7, thereby
differentially impacting placental development, function, and fetal growth. Results from Aim 1 will provide new
scientific knowledge on R4 and R7 functions in placental biology during times impractical to obtain in humans
through characterizing a robust in vivo model and placental phenotype at select gestational times. Mechanistic
in vitro studies in Aim 2 will delineate L12-mediated signaling in fetal and maternal cells.
项目总结/摘要
胎盘功能受损会导致危险的妊娠并发症,如先兆子痫、子宫内出血、
生长受限胎盘萎缩和死胎胎盘功能障碍是产妇,
胎儿和新生儿的发病率和死亡率,并使后代更容易患上
心血管疾病,2型糖尿病,胰岛素抵抗,肥胖,高血压和中风,
成年为了改善人类健康,必须阐明导致胎盘功能受损的机制,
发展趋化因子CXCL 12(L12)调节几个过程,这些过程对肿瘤的发展至关重要。
胎盘(胎盘形成),如刺激细胞增殖和迁移、血管形成、免疫细胞
通过直接作用于胎儿滋养层和母体子宫内膜的募集和细胞因子产生,
免疫细胞这些基本功能是通过L12激活其两种受体CXCR 4(R4)和/或CXCR 5(R5)而引起的。
CXCR 7(R7);然而,与R7相比,R4在胎盘形成过程中的作用仍不清楚,这表明R4在胎盘形成过程中起着重要作用。
知识上存在巨大差距。我们的研究小组和其他研究人员证明,L12介导的信号传导强烈地
与胎盘功能障碍,特别是先兆子痫病因有关。定义L12引起的行动
通过它的两个受体可以揭示导致胎盘功能障碍的潜在机制。我们开发了一个
研究胎儿(滋养层)-母体(子宫内膜)L12依赖性信号传导的创新动物模型
通过将治疗直接输送到子宫内来实现接口。我们公布的初步数据表明,
在胚胎植入的小窗口期间破坏L12介导的信号传导减少了胎盘
血管化,诱导自噬,并在后期产生过度的炎症性胎盘环境。
怀孕值得注意的是,几个观察到的结果反映了胎盘功能障碍,表明不平衡
在L12/R4/R7信号传导中可能是致病的。初步数据表明L12/R4信号传导的短暂抑制
通过先兆子痫标志物VEGF受体-1(sFLT-1)诱导持续性胎盘功能不全,
生长因子(PlGF)在妊娠中期几个月后仍升高。是否过度激活R7
当R4被抑制时对这些发现的贡献仍然不确定。我们的数据强调了
L12在胎盘形成过程中的作用,并提供了强有力的证据表明,改变L12介导的信号转导诱导持久的
妊娠后期出现的胎盘效应。然而,我们对L12,
由胎儿滋养层细胞分泌,通过滋养层和母体细胞上的R4和R7发出信号。SC 1将
测试L12通过R4与R7诱导不同生物学反应的总体假设,从而
差异性地影响胎盘发育、功能和胎儿生长。目标1的结果将提供新的
R4和R7在胎盘生物学中功能的科学知识,在人类无法获得的时期
通过在选择的妊娠时间表征稳健的体内模型和胎盘表型。机械论
目的2中的体外研究将描述胎儿和母体细胞中L12介导的信号传导。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Ryan Lynn Ashley其他文献
Ryan Lynn Ashley的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Ryan Lynn Ashley', 18)}}的其他基金
CXCL12 regulation of placental development and fetal health
CXCL12对胎盘发育和胎儿健康的调节
- 批准号:
10612945 - 财政年份:2021
- 资助金额:
$ 37万 - 项目类别:
CXCL12 regulation of placental development and fetal health
CXCL12对胎盘发育和胎儿健康的调节
- 批准号:
10090332 - 财政年份:2021
- 资助金额:
$ 37万 - 项目类别:
Full Project 3: Advancing Understanding of Hormonal Contributors to Breast Cance
完整项目 3:增进对乳腺癌激素贡献者的了解
- 批准号:
8741943 - 财政年份:
- 资助金额:
$ 37万 - 项目类别:
Full Project 3: Advancing Understanding of Hormonal Contributors to Breast Cance
完整项目 3:增进对乳腺癌激素贡献者的了解
- 批准号:
8641897 - 财政年份:
- 资助金额:
$ 37万 - 项目类别:
相似海外基金
Prediction and prevention of abruptio placentae by measurement of PAI-1
PAI-1检测预测和预防胎盘早剥
- 批准号:
25670700 - 财政年份:2013
- 资助金额:
$ 37万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Triggers of Abruptio Placentae - A Case Crossover Study of an Ischemic Placental
胎盘早剥的触发因素——缺血性胎盘的病例交叉研究
- 批准号:
8514660 - 财政年份:2010
- 资助金额:
$ 37万 - 项目类别:
Triggers of Abruptio Placentae - A Case Crossover Study of an Ischemic Placental
胎盘早剥的触发因素——缺血性胎盘的病例交叉研究
- 批准号:
8324980 - 财政年份:2010
- 资助金额:
$ 37万 - 项目类别:
Triggers of Abruptio Placentae - A Case Crossover Study of an Ischemic Placental
胎盘早剥的触发因素——缺血性胎盘的病例交叉研究
- 批准号:
7983908 - 财政年份:2010
- 资助金额:
$ 37万 - 项目类别:
Triggers of Abruptio Placentae - A Case Crossover Study of an Ischemic Placental
胎盘早剥的触发因素——缺血性胎盘的病例交叉研究
- 批准号:
8701313 - 财政年份:2010
- 资助金额:
$ 37万 - 项目类别:
Triggers of Abruptio Placentae - A Case Crossover Study of an Ischemic Placental
胎盘早剥的触发因素——缺血性胎盘的病例交叉研究
- 批准号:
8141387 - 财政年份:2010
- 资助金额:
$ 37万 - 项目类别: