UTERINE NK CELL HOMING FROM THE PERIPHERAL CIRCULATION
子宫 NK 细胞从外周循环归巢
基本信息
- 批准号:7960421
- 负责人:
- 金额:$ 14.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-01 至 2010-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdhesivesBiological AssayBiologyBlood CirculationCell Adhesion MoleculesCell-Cell AdhesionCellsCenters of Research ExcellenceComputer Retrieval of Information on Scientific Projects DatabaseEndothelial CellsEndotheliumEstrogensFetal DevelopmentFirst Pregnancy TrimesterFrozen SectionsFundingGrantHabitual AbortionHomingHost DefenseHumanIn VitroInstitutionLeadLymphocyteMaintenanceModelingMusNatural Killer CellsOvulationPerinatalPeripheralPhenotypePlacentaPlayPopulationPregnancyProgesteroneRecruitment ActivityRelative (related person)ReportingResearchResearch PersonnelResourcesRoleSourceSpiral Artery of the EndometriumStromal CellsTestingUnited States National Institutes of HealthUterusWomanadhesion receptorangiogenesisbaseexperiencefailure Implantationmigrationtrophoblast
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
Uterine Natural Killer cells (uNK) are a unique subpopulation of CD56brightCD16- lymphocytes that increase in number after ovulation, and reach their peak numbers during the first trimester of pregnancy. Although lymphocytes are generally thought to play a role in host defense, there is increasing evidence that the primary function of uNK cells is not immunological but rather they may play a role in angiogenesis, trophoblast invasion and spiral artery remodeling. Women who experience recurrent miscarriages and failure of implantation have been reported to be deficient in uNK cells. Thus proper localization and function of uNK cells is necessary for normal fetal development.
The origins of uNK cells are unclear. During pregnancy, their number expands greatly, either through increased recruitment to the uterus, or via expansion of resident populations. Approximately 10% of peripheral NK cells (pNK) are of the uNK phenotype (CD56brightCD16-), and have been proposed to be selectively recruited to the uterus during pregnancy. However, recently it has been reported that TGF¿ supports conversion of CD56dimCD16+ cells towards a CD56brightCD16- phenotype, and that decidual stromal cells produce TGF¿. Based on these findings, we hypothesize that CD56dimCD16+ pNK cells are recruited to the uterus, where they are then induced towards the CD56brightCD16- uNK phenotype by TGF¿. If this model is correct, then CD56dimCD16+ cells would be predicted to be preferentially recruited to uterine endothelium as compared to CD56brightCD16- cells. We will test this hypothesis in the following aims:
Specific Aim 1. Determine the relative adhesive ability of specific human NK cell subpopulations to frozen sections of mouse placenta.
Specific Aim 2. Utilizing cultured human uterine micrrovascular endothelial cells (HUtMVEC), examine the entire rolling-arrest-transmigration cascade of uNK recruitment and test the transmigration capability of each subpopulation. Specifically, we will (a) test the effect of estrogen, progesterone, and LH on expression of adhesion molecules by HUtMVEC in culture, to identify conditions where they are upregulated; (b) using the conditions defined from part a, establish a cell-cell adhesion assay for human NK cells with HUtMVEC; and (c) develop an in vitro flow assay using HUtMVEC induced to express adhesion receptors, and defined human NK subpopulations to recapitulate rolling, arrest and transendothelial migration in vitro.
These studies will lead to a better understanding of the origin of human uNK cells, their homing mechanism, and their role in maintenance of normal pregnancy.
这个子项目是许多研究子项目中的一个
由NIH/NCRR资助的中心赠款提供的资源。子项目和
研究者(PI)可能从另一个NIH来源获得了主要资金,
因此可以在其他CRISP条目中表示。所列机构为
研究中心,而研究中心不一定是研究者所在的机构。
子宫自然杀伤细胞(uNK)是一种独特的CD 56亮CD 16-淋巴细胞亚群,在排卵后数量增加,并在妊娠的前三个月达到高峰。 虽然淋巴细胞通常被认为在宿主防御中发挥作用,但越来越多的证据表明uNK细胞的主要功能不是免疫学的,而是它们可能在血管生成、滋养层浸润和螺旋动脉重塑中发挥作用。 据报道,经历反复流产和着床失败的妇女缺乏uNK细胞。 因此,uNK细胞的适当定位和功能对于正常的胎儿发育是必要的。
uNK细胞的起源尚不清楚。 在怀孕期间,她们的数量会大大增加,要么是通过增加子宫的招募,要么是通过扩大居住人口。 大约10%的外周NK细胞(pNK)是uNK表型(CD 56 brightCD 16-),并已提出在妊娠期间选择性地募集到子宫。 然而,最近有报道称TGF β支持CD 56 dimCD 16+细胞向CD 56 brightCD 16-表型的转化,并且蜕膜基质细胞产生TGF β。 基于这些发现,我们假设CD 56 dimCD 16 + pNK细胞被募集到子宫,在那里它们被TGF β诱导向CD 56 brightCD 16- uNK表型。 如果该模型是正确的,那么与CD 56 brightCD 16-细胞相比,CD 56 dimCD 16+细胞将被预测优先募集到子宫内皮。 我们将在以下目标中检验这一假设:
具体目标1。 测定特定人NK细胞亚群对小鼠胎盘冷冻切片的相对粘附能力。
具体目标2。 利用培养的人子宫微血管内皮细胞(HUtMVEC),检查uNK募集的整个滚动-停滞-迁移级联,并测试每个亚群的迁移能力。 具体而言,我们将(a)测试雌激素、孕酮和LH对培养物中HUtMVEC表达粘附分子的影响,以鉴定它们上调的条件;(B)使用a部分定义的条件,建立人NK细胞与HUtMVEC的细胞-细胞粘附测定;和(c)使用诱导表达粘附受体的HUtMVEC开发体外流动试验,并定义人NK亚群以概括体外滚动、停滞和跨内皮迁移。
这些研究将有助于更好地了解人类uNK细胞的起源,它们的归巢机制以及它们在维持正常妊娠中的作用。
项目成果
期刊论文数量(0)
专著数量(0)
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SUNIL K SHAW其他文献
SUNIL K SHAW的其他文献
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{{ truncateString('SUNIL K SHAW', 18)}}的其他基金
UTERINE NK CELL HOMING FROM THE PERIPHERAL CIRCULATION
子宫 NK 细胞从外周循环归巢
- 批准号:
8360544 - 财政年份:2011
- 资助金额:
$ 14.39万 - 项目类别:
UTERINE NK CELL HOMING FROM THE PERIPHERAL CIRCULATION
子宫 NK 细胞从外周循环归巢
- 批准号:
8168332 - 财政年份:2010
- 资助金额:
$ 14.39万 - 项目类别:
Cytoskeletal regulation of endothelial barrier function by WAVE2
WAVE2 对内皮屏障功能的细胞骨架调节
- 批准号:
7844951 - 财政年份:2009
- 资助金额:
$ 14.39万 - 项目类别:
Cytoskeletal regulation of endothelial barrier function by WAVE2
WAVE2 对内皮屏障功能的细胞骨架调节
- 批准号:
7589069 - 财政年份:2009
- 资助金额:
$ 14.39万 - 项目类别:
VASCULAR ENDOTHELIAL CADHERIN FUNCTION IN INFLAMMATION
炎症中的血管内皮钙粘蛋白功能
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6342413 - 财政年份:2000
- 资助金额:
$ 14.39万 - 项目类别:
VASCULAR ENDOTHELIAL CADHERIN FUNCTION IN INFLAMMATION
炎症中的血管内皮钙粘蛋白功能
- 批准号:
6032000 - 财政年份:2000
- 资助金额:
$ 14.39万 - 项目类别:
VASCULAR ENDOTHELIAL CADHERIN FUNCTION IN INFLAMMATION
炎症中的血管内皮钙粘蛋白功能
- 批准号:
6700946 - 财政年份:2000
- 资助金额:
$ 14.39万 - 项目类别:
VASCULAR ENDOTHELIAL CADHERIN FUNCTION IN INFLAMMATION
炎症中的血管内皮钙粘蛋白功能
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6489616 - 财政年份:2000
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$ 14.39万 - 项目类别:
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