Placenta-specific miR-519c-mediated induction of immune tolerance in human placenta
胎盘特异性 miR-519c 介导的人胎盘免疫耐受诱导
基本信息
- 批准号:10286082
- 负责人:
- 金额:$ 33.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-02 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAllogenicAnti-Inflammatory AgentsAttenuatedBacterial ToxinsBiological MarkersCellsClinicalDataDiseaseDistantDoseDown-RegulationEndometrialEnvironmentEquilibriumExhibitsExposure toFetusFutureGrantHistologicHost DefenseHumanImmuneImmune ToleranceImmune responseImmune systemImmunosuppressionInfectionInflammationInflammatoryInflammatory ResponseInvadedLeadLinkMaintenanceMaternal-Fetal ExchangeMediatingMicroRNAsMicrobeModelingMolecularMothersMusOrganismPathologicPhenotypePlacentaPlacentationPlayPregnancyPregnancy TrimestersPregnant WomenPremature BirthProductionResearchRoleSignal TransductionStimulusTestingTherapeuticTissuesUterine ContractionUterusWomanbiomarker identificationcandidate markercell typeexperimental studyextracellular vesiclesfetalhealthy pregnancyhuman diseaseimplantationintraamniotic infectionmortalitynovelpathogenpathogenic microbepreventtherapeutic targettissue injurytrophoblast
项目摘要
SUMMARY/ABSTRACT
Pregnancy represents a unique challenge for the maternal-fetal immune interface, requiring the balance
between immunosuppression, essential for the maintenance of semi-allogeneic fetus and pro-inflammatory
host defense to protect the mother and fetus from invading organisms. Adaptation to repeated inflammatory
stimuli may be critical in preventing rejection of the fetus by the exaggerated maternal inflammatory responses
to mild/moderate infections that are common during human pregnancy.
Immune tolerance/adaptation is a well-described phenomenon in which cells exposed to repeated
pathogens become less responsive to subsequent exposures. This adaptation suppresses an overly
aggressive inflammatory response to repeated infections that can be detrimental to the tissues rather than
protective. Dampened immune response to repeated infections has been associated with protection against
tissue injury and mortality in several human diseases. However, to date, the role of immune tolerance to
repeated infections in the context of human pregnancy, and the exact mechanisms that contribute to the
establishment of such immune adaptation to prevent inflammation-induced pathologic pregnancies are not
explored. There is now extensive evidence that miRNAs play an important role in the maintenance of a healthy
pregnancy, with a wide range of miRNAs implicated in endometrial receptivity, implantation, gestational tissues
function, and labor. Our preliminary results indicate that repeated LPS (gram negative bacterial toxins) or LTA
(gram-positive bacterial toxins) exposures to human placenta attenuates exaggerated inflammatory responses
known to contribute to inflammation-associated pathologic pregnancies. Our data also point to the involvement
of a human- and placenta-specific miRNA called miRNA-519c-3p (miR-519c) in the development of placental
immune tolerance. Our overriding hypothesis is that repeated exposure of the placenta to pathogens induces a
tolerant phenotype mediated by the miR-519c to guard the maternal-fetal interface from the exaggerated
inflammation associated with pathologic pregnancies. We hypothesize that LPS/LTA induce placental
trophoblasts to secrete miR-519c packaged within placental extracellular vesicles for delivery to nearby or
distant cells. The miR-519c within the EVs will mediate down-regulation of exaggerated pro-inflammatory
responses associated with repeated bacterial toxin exposures.
We propose the following specific aims: Aim 1: Investigate the role of miR-519c in mediating immune
adaptation in the human placenta after repeated infections and Aim 2: Investigate the molecular mechanisms
of placental miR-519c mediating immune adaptation. These studies will set the stage for future experiments to
test if decreased expression of miR-519c is linked to inflammation-associated pathologic pregnancies. This
unique human- and placenta-specific miR-519c can be an excellent biomarker candidate as well as a
therapeutic target for inflammatory diseases of pregnancy.
摘要/摘要
怀孕对母胎免疫界面来说是一个独特的挑战,需要平衡
免疫抑制,对于维持半同种异体胎儿和促炎至关重要
宿主防御,保护母亲和胎儿免受生物体的入侵。对反复炎症的适应
刺激可能对于防止胎儿因母体过度炎症反应而排斥反应至关重要
人类怀孕期间常见的轻度/中度感染。
免疫耐受/适应是一种被充分描述的现象,其中细胞暴露于重复的环境中
病原体对后续暴露的反应减弱。这种适应抑制了过度的
对重复感染的侵袭性炎症反应可能对组织有害,而不是
保护的。对重复感染的免疫反应减弱与预防感染有关
几种人类疾病中的组织损伤和死亡。然而,迄今为止,免疫耐受的作用
人类怀孕期间的反复感染,以及导致这种情况的确切机制
建立这种免疫适应来预防炎症引起的病理性妊娠并不
探索过。现在有大量证据表明 miRNA 在维持健康方面发挥着重要作用
妊娠,多种 miRNA 与子宫内膜容受性、着床、妊娠组织有关
功能、劳动。我们的初步结果表明,重复的 LPS(革兰氏阴性细菌毒素)或 LTA
(革兰氏阳性细菌毒素)接触人胎盘可减弱过度的炎症反应
已知会导致炎症相关的病理性妊娠。我们的数据也表明参与
人类和胎盘特异性 miRNA(称为 miRNA-519c-3p (miR-519c))在胎盘发育中的作用
免疫耐受。我们最重要的假设是胎盘反复暴露于病原体会诱发
由 miR-519c 介导的耐受表型,以保护母胎界面免受过度影响
与病理性妊娠相关的炎症。我们假设 LPS/LTA 诱导胎盘
滋养层细胞分泌包装在胎盘细胞外囊泡内的 miR-519c,以递送到附近或
遥远的细胞。 EV 内的 miR-519c 将介导过度促炎的下调
与反复接触细菌毒素相关的反应。
我们提出以下具体目标: 目标 1:研究 miR-519c 在介导免疫中的作用
反复感染后人类胎盘的适应和目标2:研究分子机制
胎盘 miR-519c 介导免疫适应。这些研究将为未来的实验奠定基础
测试 miR-519c 表达降低是否与炎症相关的病理性妊娠有关。这
独特的人类和胎盘特异性 miR-519c 可以成为优秀的候选生物标志物,
妊娠期炎症性疾病的治疗靶点。
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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Nazeeh N Hanna其他文献
EFFECT OF LABOR ON PLACENTAL CYTOKINE PRODUCTION: A RISK FOR HIV VERTICAL TRANSMISSION. 1022
劳动对胎盘细胞因子产生的影响:HIV 垂直传播的风险。1022
- DOI:
10.1203/00006450-199604001-01044 - 发表时间:
1996-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Nazeeh N Hanna;Surendra Sharma - 通讯作者:
Surendra Sharma
IS PREGNANCY ASSOCIATED WITH A BIAS TOWARDS TH2 TYPE CYTOKINE (CYT) PRODUCTION? † 1712
怀孕是否与偏向 TH2 型细胞因子(CYT)产生有关?†1712
- DOI:
10.1203/00006450-199604001-01736 - 发表时间:
1996-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Nazeeh N Hanna;Surendra Sharma - 通讯作者:
Surendra Sharma
Nazeeh N Hanna的其他文献
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{{ truncateString('Nazeeh N Hanna', 18)}}的其他基金
Diversity Supplement: Placenta-specific miR-519c-mediated induction of immune tolerance in human placenta - Revision - 1
多样性补充:胎盘特异性 miR-519c 介导的人胎盘免疫耐受诱导 - 修订版 - 1
- 批准号:
10833899 - 财政年份:2023
- 资助金额:
$ 33.11万 - 项目类别:
Placenta-specific miR-519c-mediated induction of immune tolerance in human placenta
胎盘特异性 miR-519c 介导的人胎盘免疫耐受诱导
- 批准号:
10290319 - 财政年份:2020
- 资助金额:
$ 33.11万 - 项目类别:
Placenta-specific miR-519c-mediated induction of immune tolerance in human placenta
胎盘特异性 miR-519c 介导的人胎盘免疫耐受诱导
- 批准号:
10406375 - 财政年份:2020
- 资助金额:
$ 33.11万 - 项目类别:
Placenta-specific miR-519c-mediated induction of immune tolerance in human placenta
胎盘特异性 miR-519c 介导的人胎盘免疫耐受诱导
- 批准号:
9885004 - 财政年份:2020
- 资助金额:
$ 33.11万 - 项目类别:
Placenta-specific miR-519c-mediated induction of immune tolerance in human placenta
胎盘特异性 miR-519c 介导的人胎盘免疫耐受诱导
- 批准号:
10611511 - 财政年份:2020
- 资助金额:
$ 33.11万 - 项目类别:
Cold milk as a novel therapy for dysphagia in preterm infants
冷牛奶作为早产儿吞咽困难的新疗法
- 批准号:
10378455 - 财政年份:2020
- 资助金额:
$ 33.11万 - 项目类别:
New Model Leading to Preterm Delivery: Role of Exposure to Environmental Toxins
导致早产的新模式:环境毒素暴露的作用
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7866647 - 财政年份:2009
- 资助金额:
$ 33.11万 - 项目类别:
New Model Leading to Preterm Delivery: Role of Exposure to Environmental Toxins
导致早产的新模式:环境毒素暴露的作用
- 批准号:
7641974 - 财政年份:2009
- 资助金额:
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