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，含有一种独特的白细胞成分。尽管 妊娠期母胎胎盘免疫相互作用的重要性 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 早孕在人类妊娠中并不是很容易研究的。对调节机制的干扰 母胎交界处蜕膜白细胞的种群维持和贩运被认为是 孕期发病率和死亡率(即先兆子痫、早产、胎儿生长受限)和 提出了一个强大的诊断和治疗目标。因此，这项R21探索/发展助学金 应用目的是建立一种新的怀孕猕猴模型，定义外周血细胞向 使用新的连续血管内染色(SIVS)技术检测蜕膜，目的如下： 具体目标1：确定蜕膜淋巴细胞的贩运和种群动态，包括 妊娠恒河猴蜕膜NK细胞。我们将检验这样一种假设，即从外围设备走私 血液和组织内常驻蜕膜淋巴细胞的增殖和凋亡驱动着种群动态 怀孕了。此外，这些淋巴细胞相对于蜕膜血管的分布将提供 洞察其贩运的功能和机制。 具体目的2.确定包括NK细胞在内的外周血淋巴细胞向 非妊娠子宫内膜。我们将检验这样一种假设，即淋巴细胞向发育中的 母胎界面在月经周期的黄体晚期开始，与是否存在无关 指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：哪些淋巴细胞活跃 怀孕期间全身血管和蜕膜滞留之间的关系？什么是细胞增殖的平衡点 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是什么？ 相对于蜕膜内的血管系统，常驻淋巴细胞？而且，是从血液贩卖到 子宫开始于黄体期，为妊娠的建立做准备？确定原点和 蜕膜淋巴细胞的动态变化对于提出其在血液学中的关键作用的假说是必要的 胎盘植入转化为临床可操作的智能。R21探索性/开发性资助机制 支持处于早期和概念阶段的研究项目。SIVS范式的应用 怀孕的非人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，这些评估贩运人口的方法 非人灵长类动物模型体内的免疫细胞将是应用于其他实验环境的强大工具， 包括妊娠感染性疾病、造血干细胞和实体器官移植。