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，妊娠驱动的人群 蜕膜白细胞的动态一直难以确定，从月经周期到 在人类妊娠中，不容易研究早期妊娠。调节机制紊乱 母体-胎儿界面的蜕膜白细胞的群体维持和运输被认为 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 提供了一个强大的诊断和治疗靶点。因此，这项R21探索/发展补助金 本申请的目的是建立一种新的妊娠猕猴模型，该模型定义了外周血细胞向 使用具有以下特定目的的连续血管内染色（SIVS）新技术对蜕膜进行染色。 具体目标1：确定蜕膜淋巴细胞的运输和群体动力学，包括 蜕膜NK细胞，在怀孕的恒河猴。我们将检验一个假设， 血液和增殖和细胞凋亡的组织驻留蜕膜淋巴细胞驱动人口动态跨越 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 深入了解其职能和贩运机制。 具体目标2。为了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这样一个假设，即淋巴细胞向发育中的 母胎界面在月经周期的黄体晚期启动，与是否存在无关 胚胎或胎盘发育的。 我们提出的研究将回答以下基本问题： 系统性血管和妊娠期间蜕膜驻留之间的关系？细胞增殖的平衡是什么 和整个妊娠期蜕膜驻留淋巴细胞的细胞死亡？贩运人口的分布情况如何， 相对于蜕膜内的脉管系统，是否存在常驻淋巴细胞？从血液到 子宫在黄体期开始为怀孕做准备？确定起源和 蜕膜淋巴细胞的动力学是必要的，以推进其在血绒膜中的关键作用的假设。 转化为临床上可操作的智能。R21探索/发展补助金机制 在早期和概念阶段支持研究项目。SIVS范式在 怀孕的非人类灵长类动物模型可能对我们理解生殖系统产生重大影响。 母胎界面的免疫学。此外，这些评估贩运人口的方法， 非人灵长类动物模型中的体内免疫细胞将是应用于其他实验环境的有力工具， 包括妊娠期感染性疾病、造血干细胞移植和实体器官移植。