CXCL12 regulation of placental development and fetal health

CXCL12对胎盘发育和胎儿健康的调节

基本信息

批准号：
10405420
负责人：
Ryan Lynn Ashley
金额：
$ 37万
依托单位：
NEW MEXICO STATE UNIVERSITY LAS CRUCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-17 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10405420
关键词：
AMD3100 Abruptio Placentae Adult Amniotic Fluid Animal Model Autophagocytosis Biological Blood Pressure CRISPR/Cas technology CXCL12 gene CXCR4 gene Cardiovascular Diseases Cell Proliferation Cell Survival Cells Comprehension Dangerousness Data Development Dissection Endometrial Environment Etiology Event Fetal Growth Fetal Growth Retardation Fetal health Foundations Functional disorder Funding Generations Growth Growth Factor Health Human Hypertension Immune Impairment In Vitro Inflammatory Insulin Resistance KDR gene Knowledge Maternal-Fetal Exchange Measures Mediating Methods Modeling Molecular Morbidity - disease rate Neonatal Mortality Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome PGF gene Pathogenesis Pathologic Pathology Perfusion Pharmacological Treatment Phenotype Placenta Placental Biology Placental Insufficiency Placentation Plant Roots Plasma Play Positioning Attribute Pre-Eclampsia Pregnancy Pregnancy Complications Process Production Productivity Proteome Publications Publishing Regulation Research Role Signal Transduction Solid Source Stimulation of Cell Proliferation Stroke Testing Time United States National Institutes of Health Uterus Vascularization cell motility chemokine cytokine fetal high risk implantation improved in vivo Model inhibitor innovation insight migration mortality natural Blastocyst Implantation neonatal morbidity novel therapeutics offspring potential biomarker receptor receptor expression recruit response skills stillbirth success trophoblast

项目摘要

Project Summary/Abstract Impaired placental function leads to dangerous pregnancy complications such as preeclampsia, intrauterine growth restriction, placental abruption, and stillbirth. Placental dysfunction is the leading cause of maternal, fetal, and neonatal morbidity and mortality worldwide and predisposes offspring to higher risks of developing cardiovascular disease, type 2 diabetes, insulin resistance, obesity, hypertension, and stroke during adulthood. To improve human health, it is imperative to elucidate the mechanisms causing impaired placental development. The chemokine, CXCL12 (L12) regulates several processes central to the development of the placenta (placentation) such as stimulating cell proliferation and migration, vascularization, immune cell recruitment and cytokine production through direct actions on fetal trophoblast and maternal endometrial and immune cells. These essential functions are elicited via L12 activating its two receptors, CXCR4 (R4) and/or CXCR7 (R7); however, the contributions of R4 compared to R7 during placentation remain unclear, denoting a substantial gap in knowledge. Our group and others demonstrated L12-mediated signaling is strongly implicated in placental dysfunction and specifically preeclampsia etiology. Defining L12-induced actions through its two receptors may reveal underlying mechanisms causing placental dysfunction. We developed an innovative animal model to study L12-dependent signaling at the fetal (trophoblast)-maternal (endometrial) interface by delivering treatments directly into the uterus. Our published and preliminary data demonstrate disrupting L12-mediated signaling during the small window of embryo implantation diminishes placental vascularization, induces autophagy, and creates an excessive inflammatory placental environment later in gestation. Notably, several observed outcomes mirror those of placental dysfunction, suggesting an imbalance in L12/R4/R7 signaling may be causative. Preliminary data indicate transitory suppression of L12/R4 signaling induces lasting placental insufficiency with preeclampsia markers VEGF receptor-1 (sFLT-1) and placental growth factor (PlGF) remaining elevated months later, at midgestation. Whether excessive R7 activation contributes to these findings when R4 is suppressed remains uncertain. Our data underscore the importance of L12 during placentation and provide strong evidence that altering L12-mediated signaling induces enduring placental effects manifesting later in gestation. Nevertheless, we lack a clear understanding of how L12, excreted by fetal trophoblast cells, signals through R4 and R7 on trophoblast and maternal cells. This SC1 will test the overall hypothesize that L12 induces distinct biological responses through R4 versus R7, thereby differentially impacting placental development, function, and fetal growth. Results from Aim 1 will provide new scientific knowledge on R4 and R7 functions in placental biology during times impractical to obtain in humans through characterizing a robust in vivo model and placental phenotype at select gestational times. Mechanistic in vitro studies in Aim 2 will delineate L12-mediated signaling in fetal and maternal cells.

项目概要/摘要胎盘功能受损会导致危险的妊娠并发症，例如先兆子痫、宫内妊娠生长受限、胎盘早剥和死产。胎盘功能障碍是产妇发生以下疾病的主要原因：全世界胎儿和新生儿的发病率和死亡率，并使后代面临更高的患病风险心血管疾病、2型糖尿病、胰岛素抵抗、肥胖、高血压和中风成年期。为了改善人类健康，必须阐明导致胎盘受损的机制发展。趋化因子 CXCL12 (L12) 调节对细胞发育至关重要的几个过程胎盘（placentation）如刺激细胞增殖和迁移、血管化、免疫细胞通过直接作用于胎儿滋养层和母体子宫内膜来募集和产生细胞因子免疫细胞。这些基本功能是通过 L12 激活其两个受体 CXCR4 (R4) 和/或 CXCR7（R7）；然而，与 R7 相比，R4 在胎盘形成过程中的贡献仍不清楚，这表明知识上的巨大差距。我们的小组和其他人证明 L12 介导的信号传导是强烈的涉及胎盘功能障碍，特别是先兆子痫的病因。定义 L12 引发的动作通过其两个受体可能揭示导致胎盘功能障碍的潜在机制。我们开发了一个研究胎儿（滋养层）-母体（子宫内膜）L12 依赖性信号传导的创新动物模型通过将治疗直接输送到子宫中来实现界面。我们公布的初步数据表明在胚胎植入的小窗口期间破坏 L12 介导的信号传导会减少胎盘血管形成，诱导自噬，并在后期产生过度炎症的胎盘环境妊娠。值得注意的是，一些观察到的结果反映了胎盘功能障碍的结果，表明不平衡 L12/R4/R7 信号传导中的 L12/R4/R7 信号传导可能是致病原因。初步数据表明 L12/R4 信令暂时受到抑制通过先兆子痫标记物 VEGF 受体 1 (sFLT-1) 和胎盘诱导持久胎盘功能不全几个月后，在妊娠中期，生长因子（PlGF）仍然升高。 R7激活是否过度当 R4 被抑制时，对这些发现的贡献仍不确定。我们的数据强调了重要性胎盘期间 L12 的变化，并提供强有力的证据表明改变 L12 介导的信号传导可诱导持久的胎盘效应在妊娠后期显现。然而，我们对 L12、由胎儿滋养层细胞排泄，通过滋养层和母体细胞上的 R4 和 R7 发出信号。这个 SC1 将检验 L12 通过 R4 与 R7 诱导不同生物反应的总体假设，从而对胎盘发育、功能和胎儿生长有不同的影响。目标 1 的结果将提供新的关于 R4 和 R7 在胎盘生物学中的功能的科学知识在人类中无法获得通过表征稳健的体内模型和选定妊娠时间的胎盘表型。机械论目标 2 中的体外研究将描述胎儿和母体细胞中 L12 介导的信号传导。