Decidual NK response to infection
蜕膜 NK 对感染的反应
基本信息
- 批准号:10160812
- 负责人:
- 金额:$ 83.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-19 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AllogenicAwarenessBacteriaBlood VesselsCell DeathCellsConflict (Psychology)CytomegalovirusCytoplasmic GranulesCytosolCytotoxic T-LymphocytesDataDeciduaDecidual CellFetal DistressFetal Growth RetardationFetal TissuesFetusFirst Pregnancy TrimesterGoalsGranzymeHumanImmuneImmune systemImmunityInfectionInvadedLeadLigandsListeria monocytogenesLymphocyteLymphocyte SubsetMaternal-Fetal ExchangeMediatingMembraneMicrobeMusNanotubesNatural ImmunityNatural Killer CellsParasitesPathway interactionsPlacentaPlacentationPopulationPre-EclampsiaPregnancyPregnancy ComplicationsPregnancy OutcomePremature BirthPremature LaborProcessRoleSideSpontaneous abortionStreptococcus Group BT-LymphocyteTestingTissuesToxoplasma gondiiTransgenic MiceTransgenic OrganismsVascular blood supplyVirusadaptive immunityantimicrobial peptidecell killingcell typeclinically significantcongenital anomalycytokinecytotoxicextracellularfetalfetal immunityfetal lossfetus cellfungusgranulysinimmune functionimmunological synapsein vivoinsightintrauterine infectionmicrobialmigrationnovelpathogenperforinperipheral bloodplacental infectionpreventreceptorresponsetransmission processtrophoblastunborn child
项目摘要
Decidual NK cells (dNK), the largest population of maternal immune cells at the maternal-fetal interface in the
first trimester of pregnancy, directly contact fetal extravillous trophoblasts (EVT), which invade the decidua to
remodel the vasculature to establish the blood supply to the placenta. The direct contact between dNK and EVT
challenges the maternal immune system, which must tolerate fetal cells, but still protect against infection. How
dNK protect the placenta and fetus from infection is not well understood. Most clinically significant infections of
the placenta and fetus are caused by intracellular pathogens (bacteria, parasites and viruses), for which killer
lymphocytes (NK and cytotoxic T lymphocytes) are key to systemic protective immunity. In the first trimester,
when infection has the most serious fetal consequences, there are few T cells in the decidua. Although dNK
have cytotoxic granules, express all the cytotoxic molecules, and kill conventional NK cell targets, their cytolytic
activity is reduced compared to peripheral blood NK cells. Moreover, although dNK form contacts with EVT, they
do not degranulate or kill
human cytomegalovirus-infected EVT. These findings emphasize the difficulties of
maternal immune cells to clear placental infections and prevent transmission of pathogens to the unborn child.
This proposal investigates a novel and exciting mechanism we recently discovered by which dNK kill L.
monocytogenes (Lm) inside trophoblasts, without killing the host cell. dNK express large amounts of granulysin
(GNLY), an antimicrobial peptide found both in cytotoxic granules and the cytosol that preferentially disrupts
microbial, relative to mammalian, membranes. Our preliminary data suggest that dNK establish nanotube
cytoplasmic connections to EVT. Without forming a conventional immune synapse or degranulating, dNK
transfer GNLY via nanotubes to EVT, but not other cytotoxic molecules (perforin, granzymes), which would kill
the host cell. This mechanism provides an elegant solution to the immune dilemma of pregnancy – defense
against infection while maintaining tolerance of the fetus and placenta. As far as we are aware, this is the first
evidence for an immune function of nanotubes. Nanotube transfer of GNLY and potentially other bioactive
molecules from dNK to EVT helps control intracellular infection and could regulate trophoblast functions. Our
goals are to confirm our preliminary data showing that intracellular microbes, but not fetal cells, are killed by
dNK transfer of GNLY, independently of perforin and granzymes; identify which infected maternal and fetal cells
in the placenta dNK protect and by what mechanism; explore the mechanism responsible for nanotube
formation, which molecules are transferred and which pathogens important in pregnancy are susceptible. The
protective role of GNLY and dNK will also be evaluated in human placental tissue explants and in mice by
comparing pregnancy outcomes following infection of GNLY-transgenic (Tg) and WT mice, which do not
express GNLY. These explant and in vivo studies will investigate three pathogens of pregnancy - Lm, Group B
Streptococci (GBS) and Toxoplasma gondii.
蜕膜NK细胞(DNK),母胎界面最大的母体免疫细胞群
妊娠早期,直接接触胎儿绒毛外滋养细胞(EVT),它侵入蜕膜以
重建血管系统以建立对胎盘的血液供应。DNK与EVT的直接接触
挑战母体免疫系统,母体免疫系统必须耐受胎儿细胞,但仍能保护免受感染。多么
DNK保护胎盘和胎儿免受感染的机制尚不清楚。临床上最有意义的感染
胎盘和胎儿是由细胞内的病原体(细菌、寄生虫和病毒)引起的,针对这些病原体的杀手
淋巴细胞(NK和细胞毒性T淋巴细胞)是系统保护性免疫的关键。在怀孕的前三个月,
当感染对胎儿造成最严重的后果时,蜕膜中的T细胞很少。虽然DNK
有细胞毒颗粒,表达所有的细胞毒分子,并杀伤常规的NK细胞靶点,其杀伤细胞
与外周血NK细胞相比,其活性降低。此外,尽管DNK与EVT建立了联系,但他们
不要脱颗粒或杀戮
人巨细胞病毒感染的EVT。这些发现强调了
母体免疫细胞清除胎盘感染,防止病原体传播给未出生的婴儿。
这一提议研究了我们最近发现的一种新颖而令人兴奋的机制,即DNK通过这种机制杀死L.
滋养层内的单核细胞增多症(LM),而不会杀死宿主细胞。DNK表达大量颗粒溶素
(GNLY),一种在细胞毒颗粒和胞浆中都发现的抗菌肽,它优先破坏
相对于哺乳动物而言,微生物的膜。我们的初步数据表明,DNK建立了纳米管
与室上性心动过速的细胞质连接。没有形成常规的免疫突触或脱颗粒,DNK
通过纳米管将GNLY转移到EVT,但不转移其他细胞毒性分子(穿孔素、颗粒酶),这将杀死
宿主细胞。这一机制为妊娠防御的免疫困境提供了一个很好的解决方案
抗感染,同时保持对胎儿和胎盘的耐受性。据我们所知,这是第一次
纳米管具有免疫功能的证据。纳米管转移GNLY和潜在的其他生物活性
从DNK到EVT的分子有助于控制细胞内感染,并可以调节滋养层功能。我们的
目标是证实我们的初步数据显示,细胞内的微生物,而不是胎儿细胞,被
不依赖穿孔素和颗粒酶的GNLY的DNK转移;识别哪些被感染的母婴细胞
DNK在胎盘中的保护作用及通过什么机制;探讨纳米管的作用机制
形成,哪些分子被转移,哪些病原体在怀孕中重要是易感的。这个
GNLY和DNK在人胎盘组织外植体和小鼠体内的保护作用也将通过以下方法进行评估
比较GNLY转基因(TG)小鼠和未感染的WT小鼠的妊娠结局
快递GNLY。这些外植体和体内研究将调查怀孕的三种病原体--LM,B组
链球菌(GBS)和弓形虫。
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 }}
Judy Lieberman其他文献
Judy Lieberman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('Judy Lieberman', 18)}}的其他基金
Tumor-targeted disruption of mismatch repair in microsatellite stable colorectal cancer
微卫星稳定结直肠癌中错配修复的肿瘤靶向破坏
- 批准号:
10578049 - 财政年份:2022
- 资助金额:
$ 83.58万 - 项目类别:
Mechanistic elucidation of inflammasome assembly and regulation. Supplement: Testing drugs that curtail inflammasome activation to suppress SARS-CoV-2 pathogenesis
炎症小体组装和调节的机制阐明。
- 批准号:
10159600 - 财政年份:2020
- 资助金额:
$ 83.58万 - 项目类别:
Endogenous ligand of the NK activating receptor NKp46
NK 激活受体 NKp46 的内源性配体
- 批准号:
10116279 - 财政年份:2020
- 资助金额:
$ 83.58万 - 项目类别:
Granulysin, Granzymes and Perforin in Bacterial Immune Defense
细菌免疫防御中的颗粒溶素、颗粒酶和穿孔素
- 批准号:
9222706 - 财政年份:2016
- 资助金额:
$ 83.58万 - 项目类别:
Control of placental infection by decidual NK cell secreted granulysin
蜕膜NK细胞分泌颗粒溶素控制胎盘感染
- 批准号:
9236206 - 财政年份:2016
- 资助金额:
$ 83.58万 - 项目类别:
Control of placental infection by decidual NK cell secreted granulysin
蜕膜NK细胞分泌颗粒溶素控制胎盘感染
- 批准号:
9092639 - 财政年份:2016
- 资助金额:
$ 83.58万 - 项目类别:
相似海外基金
Cultivating Diversity Awareness in Japanese Med Schools with a foreign Standardized Patient program
通过外国标准化患者计划培养日本医学院的多样性意识
- 批准号:
24K13361 - 财政年份:2024
- 资助金额:
$ 83.58万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Multi-dimensional quantum-enabled sub-THz Space-Borne ISAR sensing for space domain awareness and critical infrastructure monitoring - SBISAR
用于空间域感知和关键基础设施监测的多维量子亚太赫兹星载 ISAR 传感 - SBISAR
- 批准号:
EP/Y022092/1 - 财政年份:2024
- 资助金额:
$ 83.58万 - 项目类别:
Research Grant
Postdoctoral Fellowship: STEMEdIPRF: Examining how faculty awareness of systemic barriers and growth mindset influences students' belonging, self-efficacy, and success in STEM
博士后奖学金:STEMEdIPRF:研究教师对系统性障碍和成长心态的认识如何影响学生的归属感、自我效能和 STEM 成功
- 批准号:
2327319 - 财政年份:2024
- 资助金额:
$ 83.58万 - 项目类别:
Standard Grant
I-Corps: Virtual Reality Training Platform for Increasing Awareness of Unconscious Bias in Industry Decision-Making
I-Corps:虚拟现实培训平台,用于提高行业决策中无意识偏见的意识
- 批准号:
2402141 - 财政年份:2024
- 资助金额:
$ 83.58万 - 项目类别:
Standard Grant
CAREER: Digital Twins of Surgical Environments for Situational Awareness and Immersive Simulation
职业:用于态势感知和沉浸式模拟的手术环境数字孪生
- 批准号:
2239077 - 财政年份:2023
- 资助金额:
$ 83.58万 - 项目类别:
Continuing Grant
Development of Informatics Materials with an Awareness of the High School-University connection and a Learning Support Environment for Data-Driven Instruction
开发具有高中与大学联系意识的信息学材料和数据驱动教学的学习支持环境
- 批准号:
23H01019 - 财政年份:2023
- 资助金额:
$ 83.58万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
STTR Phase I: Space Debris Awareness Spectrum
STTR 第一阶段:空间碎片意识频谱
- 批准号:
2227213 - 财政年份:2023
- 资助金额:
$ 83.58万 - 项目类别:
Standard Grant
A smartphone rip-detection tool to improve rip current awareness
智能手机撕裂检测工具,可提高撕裂电流感知能力
- 批准号:
LP220200780 - 财政年份:2023
- 资助金额:
$ 83.58万 - 项目类别:
Linkage Projects
The 'Long COVID Education and Awareness Hub': A digitally integrated resource for patients, caregivers, and health care providers
“长期新冠病毒教育和意识中心”:为患者、护理人员和医疗保健提供者提供的数字集成资源
- 批准号:
495218 - 财政年份:2023
- 资助金额:
$ 83.58万 - 项目类别:
Evidence-Based Dialogue to Promote Sun Protection, Foster a Community of Concern and Increase Awareness for Skin Cancers in Canada.
在加拿大开展基于证据的对话,以促进防晒、培养关注社区并提高对皮肤癌的认识。
- 批准号:
485622 - 财政年份:2023
- 资助金额:
$ 83.58万 - 项目类别:
Miscellaneous Programs














{{item.name}}会员




