UTERINE NK CELL HOMING FROM THE PERIPHERAL CIRCULATION

子宫 NK 细胞从外周循环归巢

• 批准号: 7960421
• 负责人: SUNIL K SHAW
• 金额: $ 14.39万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/7960421
• 关键词: Adhesives; Biological Assay; Biology; Blood Circulation; Cell Adhesion Molecules; Cell-Cell Adhesion; Cells; Centers of Research Excellence; Computer Retrieval of Information on Scientific Projects Database; Endothelial Cells; Endothelium; Estrogens; Fetal Development; First Pregnancy Trimester; Frozen Sections; Funding; Grant; Habitual Abortion; Homing; Host Defense; Human; In Vitro; Institution; Lead; Lymphocyte; Maintenance; Modeling; Mus; Natural Killer Cells; Ovulation; Perinatal; Peripheral; Phenotype; Placenta; Play; Population; Pregnancy; Progesterone; Recruitment Activity; Relative (related person); Reporting; Research; Research Personnel; Resources; Role; Source; Spiral Artery of the Endometrium; Stromal Cells; Testing; United States National Institutes of Health; Uterus; Woman; adhesion receptor; angiogenesis; base; experience; failure Implantation; migration; trophoblast

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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 子宫天然杀伤细胞（UNK）是CD56BrightCD16-淋巴细胞的独特亚群，排卵后数量增加，并在怀孕的前三个月达到峰值。尽管通常认为淋巴细胞在宿主防御中起作用，但越来越多的证据表明，UNK细胞的主要功能不是免疫学，而是它们可能在血管生成，滋养细胞侵袭和螺旋动脉重塑中起作用。据报道，经历反复流产和植入失败的妇女在UNK细胞中缺乏。对于正常的胎儿发育是必要的，UNK细胞的适当定位和功能是必要的。 UNK细胞的起源尚不清楚。在怀孕期间，通过增加对子宫的招募或扩大居民人口的招募，它们的数量大大扩展。大约10％的外围NK细胞（PNK）为UNK表型（CD56BrightCD16-），并已提议在怀孕期间选择到子宫。但是，最近有报道称，TGF支持CD56DIMCD16+细胞向CD56BrightCD16-表型的转化，并决定产生TGFF的基质细胞。根据这些发现，我们假设CD56DIMCD16+ PNK细胞被募集到子宫，然后将它们诱导到CD56BrightCD16- UNK表型，由TGF。如果该模型正确，则与CD56BrightCD16-细胞相比，预计CD56DIMCD16+细胞被预测为子宫内皮。我们将在以下目的中检验这一假设： 具体目的1。确定特定人类NK细胞亚群对小鼠骨肉的冷冻切片的相对粘合能力。 具体目的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 - 递送转移级联并测试每个亚群的传输能力。具体而言，我们将（a）测试雌激素，孕激素和LH对培养物中HutMVEC粘合分子表达的影响，以确定其更新的条件； （b）使用由A部分定义的条件，为HUTMVEC建立人NK细胞的细胞细胞粘合剂； （c）使用诱导的HUTMVEC进行体外流量测定，并定义了人类NK亚群来概括体外滚动，停滞和跨性皮的迁移。 这些研究将使人们对人UNK细胞的起源，其归巢机制以及它们在维持正常妊娠中的作用有更好的了解。