Gestationally driven trafficking of decidual lymphocytes assessed by serial intravascular staining

通过连续血管内染色评估妊娠驱动的蜕膜淋巴细胞运输

• 批准号: 10645445
• 负责人: Aleksandar Stanic-Kostic
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645445
• 关键词: Apoptosis; Applications Grants; Architecture; Blood; Blood Cells; Cell Death; Cell Proliferation; Cells; Chemotaxis; Clinical; Communicable Diseases; Decidua; Development; Diagnostic; Embryo; Endometrial; Endometrium; Equilibrium; Exploratory/Developmental Grant; Fetal Growth; Fetal Growth Retardation; Fetus; Growth Factor; Hematopoietic stem cells; Hemochorial Placental Development; Human; Immune; Immune Tolerance; Immunologics; Infectious Agent; Intelligence; Knowledge; Leukocytes; Listeria monocytogenes; Luteal Phase; Lymphocyte; Lymphoid; Macaca; Macaca mulatta; Maintenance; Maternal-Fetal Exchange; Menstrual cycle; Methodology; Modeling; Morbidity - disease rate; Mucous Membrane; Natural Killer Cells; Organ Transplantation; Peripheral Blood Lymphocyte; Phenotype; Placenta; Population; Population Dynamics; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Labor; Preparation; Production; Proliferating; Regulatory T-Lymphocyte; Reproductive Immunology; Research; Research Project Grants; Research Support; Residencies; Risk; Role; Side; Site; Solid; Spiral Artery of the Endometrium; Stains; Surface; Techniques; Testing; Therapeutic; Tissues; Translating; United States National Institutes of Health; Uterus; Zika Virus; angiogenesis; clinically actionable; early pregnancy; experience; fetal; immune function; in vivo; insight; interest; lymphocyte trafficking; mortality; mucosal site; nonhuman primate; novel; novel strategies; peripheral blood; pregnant; pressure; reproductive tract; residence; response; therapeutic target; tool; trafficking; trophoblast

The decidua is a specially modified mucosa that harbors a unique composition of leukocytes. Despite the importance of maternal-fetoplacental immune interactions during pregnancy, the gestationally-driven population dynamics of decidual leukocytes has been difficult to ascertain, and the transition from the menstrual cycle to early pregnancy is not readily studied in human pregnancy. Disturbance of the mechanisms that regulate population maintenance and trafficking of decidual leukocytes at the maternal-fetal interface is thought to underlie morbidity and mortality in pregnancy (i.e., preeclampsia, preterm labor, fetal growth restriction) and presents a powerful diagnostic and therapeutic target. Thus, this R21 Exploratory/Developmental Grant application aims to establish a novel pregnant macaque model defining trafficking of peripheral blood cells to the decidua using the novel technique of serial intravascular staining (SIVS) with the following Specific Aims. Specific Aim 1: To determine the trafficking and population dynamics of decidual lymphocytes, including decidual NK cells, in pregnant rhesus monkeys. We will test the hypothesis that trafficking from the peripheral blood and proliferation and apoptosis of tissue-resident decidual lymphocytes drive population dynamics across pregnancy. Further, the distribution of these lymphocytes with respect to the decidual vasculature will provide insight into their function and mechanisms of trafficking. Specific Aim 2. To determine the trafficking of peripheral blood lymphocytes, including NK cells, to the nonpregnant endometrium. We will test the hypothesis that the trafficking of lymphocytes to the developing maternal-fetal interface is initiated in the late luteal phase of the menstrual cycle, independent of the presence of an embryo or developing placenta. Our proposed studies will answer the following fundamental questions: Which lymphocytes actively traffic between systemic vasculature and decidual residency during pregnancy? What is the balance of cell proliferation and cell death of decidua-resident lymphocytes across gestation? What is the distribution of trafficking and resident lymphocytes relative to the vasculature within the decidua? And, is trafficking from the blood to the uterus initiated in the luteal phase in preparation for the establishment of pregnancy? Determining the origin and dynamics of decidual lymphocytes is necessary to advance the hypothesis of their pivotal role in hemochorial placentation into clinically actionable intelligence. The R21 Exploratory/Developmental Grant mechanism supports research projects in their early and conceptual stages. The application of the SIVS paradigm to the pregnant nonhuman primate model could have a major impact on our understanding of the reproductive immunology of the maternal-fetal interface. Furthermore, these methodologies for assessing trafficking of immune cells in vivo in the nonhuman primate model will be powerful tools to apply to other experimental settings, including infectious disease in pregnancy and hematopoietic stem cell and solid organ transplantation.

蜕膜是一种经过特殊修饰的粘膜，含有独特的白细胞成分。尽管 妊娠期间母胎胎盘免疫相互作用的重要性，妊娠驱动人群 蜕膜白细胞的动态很难确定，从月经周期到月经周期的转变 早期妊娠尚未在人类妊娠中进行研究。调节机制受到干扰 母胎界面处的群体维持和蜕膜白细胞的运输被认为是 妊娠期发病率和死亡率的基础（即先兆子痫、早产、胎儿生长受限）和 提供了强大的诊断和治疗靶点。因此，这项 R21 探索性/发展补助金 该申请旨在建立一种新型怀孕猕猴模型，定义外周血细胞向 使用连续血管内染色 (SIVS) 新技术进行蜕膜检测，其具体目标如下。 具体目标 1：确定蜕膜淋巴细胞的运输和群体动态，包括 怀孕恒河猴的蜕膜 NK 细胞。我们将检验以下假设：来自外围国家的贩运 血液以及组织驻留蜕膜淋巴细胞的增殖和凋亡驱动跨区域的群体动态 怀孕。此外，这些淋巴细胞相对于蜕膜脉管系统的分布将提供 深入了解其功能和贩运机制。 具体目标 2. 确定外周血淋巴细胞（包括 NK 细胞）向 非妊娠子宫内膜。我们将检验以下假设：淋巴细胞运输至发育中的细胞 母胎界面在月经周期的黄体期晚期开始，与是否存在无关 胚胎或发育中的胎盘。 我们提出的研究将回答以下基本问题：哪些淋巴细胞主动运输 怀孕期间全身脉管系统和蜕膜驻留之间的关系？什么是细胞增殖的平衡 以及妊娠期间蜕膜驻留淋巴细胞的细胞死亡？人口贩运的分布情况如何？ 相对于蜕膜内脉管系统的常驻淋巴细胞？并且，是从血液贩运到 子宫在黄体期启动，为怀孕做准备？确定原产地和 蜕膜淋巴细胞的动力学对于推进其在血绒毛膜中关键作用的假设是必要的 植入临床可操作的情报。 R21 探索性/发展性资助机制 支持早期和概念阶段的研究项目。 SIVS范式的应用 怀孕的非人类灵长类动物模型可能会对我们对生殖的理解产生重大影响 母胎界面的免疫学。此外，这些评估贩卖人口的方法 非人类灵长类动物模型中的体内免疫细胞将成为应用于其他实验环境的强大工具， 包括妊娠期感染性疾病和造血干细胞及实体器官移植。