Natural killer cells in mouse pregnancy and in circulatory regulation

自然杀伤细胞在小鼠妊娠和循环调节中的作用

• 批准号: 3219-2011
• 负责人: Croy, Anne
• 金额: $ 6.89万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=568281
• 关键词: Natural; killer; cells; mouse; pregnancy

Major cardiovascular adaptations occur rapidly in healthy pregnancy. We found that pregnancy in NK-T-B- and NK+T-B- mice induces abnormal maternal heart structure and function. Anomalous uterine arterial, placental and fetal circulatory parameters were also found, leading to our postulate that NK cells and T cells contribute to circulatory regulation during pregnancy. NK and T cells express all members of the renin-angiotensin system, the major long term controller of arterial pressure (BP). Sex-specific and pregnancy time-course studies are proposed in 4 specific Aims to address the hemodynamic actions of lymphocytes and their regulation. This research is globally significant since ~15% of pregnancies have abnormal cardiovascular issues yet we lack insight to homeostatic contributions from ubiquitous lymphocytes. We have a congenic mouse panel (NK+T+B+; NK-T+B+; NK+T-B- and NK-T-B-) and mastery of radiotelemetry and micro-ultrasound to enable these studies and our preliminary work suggests structural and functional roles for lymphocytes on maternal and fetal hearts. In Aim 1, hemodynamic regulatory contributions of NK cells will be sought by comparing diet and drug induced pressor responses in males and non pregnant females of the 4 genotypes by continuous radiotelemetry. In Aim 2, NK cell roles in circulatory structure and function will be defined across pregnancy in NK-T+B+ mice using radiotelemetry, micro-ultrasound and histomorphometry. This aim will also ask if the conceptus or the mother patterns normal gestational shifts in BP and by what mechanisms. In Aim 3, mechanisms that position the 2 newly described uNK cell subsets within the spiral arterial (SA) vasculature and trigger interferon gamma (Ifng) synthesis by uNK cells will be sought. In Aim 4, genes targeted in stromal cells (3 SA-associated cell lineages) by uNK cell-derived Ifng will be identified to develop an integrated model of uNK cell-triggered steps in SA modification. Information gained from these studies will be valuable in understanding how NK cells and T cells contribute to circulatory homeostasis and if their functions include gestational programming of normal cardiovascular responses.

在健康妊娠期，主要的心血管适应发生迅速。我们发现NK-T-B和NK+T-B小鼠妊娠可引起母体心脏结构和功能异常。异常子宫动脉，胎盘和胎儿循环参数也被发现，导致我们的假设NK细胞和T细胞有助于循环调节在怀孕期间。NK细胞和T细胞表达肾素-血管紧张素系统的所有成员，肾素-血管紧张素系统是动脉压（BP）的主要长期控制者。在4个特定的目的中提出了性别特异性和妊娠期的研究，以解决淋巴细胞的血流动力学作用及其调节。这项研究具有全球意义，因为约15%的孕妇有心血管异常问题，但我们缺乏对无处不在的淋巴细胞对体内平衡的贡献的了解。我们有一个同源小鼠小组（NK+T+B+; NK-T+B+； NK+T-B-和NK-T-B-），掌握了无线电遥测和微超声，使这些研究成为可能，我们的初步工作表明淋巴细胞在母体和胎儿心脏中的结构和功能作用。在Aim 1中，通过连续无线电遥测，通过比较4种基因型男性和未怀孕女性的饮食和药物诱导的升压反应，寻求NK细胞的血流动力学调节作用。在Aim 2中，NK细胞在NK- t +B+小鼠妊娠期间循环结构和功能中的作用将通过无线电遥测、微超声和组织形态学来确定。这一目的还将询问孕妇或母亲是否在血压中出现正常的妊娠变化，以及通过什么机制。在Aim 3中，将寻求将2种新描述的uNK细胞亚群定位在螺旋动脉（SA）血管中并触发uNK细胞合成干扰素γ (Ifng)的机制。在Aim 4中，将鉴定由uNK细胞衍生的Ifng靶向基质细胞（3个SA相关细胞系）的基因，以建立一个uNK细胞触发SA修饰步骤的集成模型。从这些研究中获得的信息将有助于了解NK细胞和T细胞如何促进循环稳态，以及它们的功能是否包括妊娠期正常心血管反应的编程。