CXCL12 regulation of placental development and fetal health

项目摘要/摘要 胎盘功能受损会导致危险的妊娠并发症，如先兆子痫、宫内 生长受限、胎盘早剥和死产。胎盘功能障碍是母体的主要原因， 世界各地的胎儿和新生儿发病率和死亡率，并使后代更容易患上更高的风险 心血管疾病、2型糖尿病、胰岛素抵抗、肥胖、高血压和中风 成人期。为了改善人类健康，有必要阐明导致胎盘受损的机制。 发展。趋化因子CXCL12(L12)调节几个过程，这些过程对肿瘤的发展至关重要。 胎盘(胎盘)，如刺激细胞增殖和迁移、血管形成、免疫细胞 通过对胎儿滋养细胞和母体子宫内膜的直接作用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，R4与R7在胎盘形成过程中的作用尚不清楚，这意味着 知识上的巨大差距。我们的团队和其他人证明了L12介导的信号转导强烈 与胎盘功能障碍有关，尤其与子痫前期的病因有关。定义L12诱导的操作 通过它的两个受体可能揭示导致胎盘功能障碍的潜在机制。我们开发了一种 研究胎儿(滋养细胞)-母体(子宫内膜)L12依赖信号的创新动物模型 通过将治疗直接输送到子宫进行接口。我们公布的和初步的数据表明 在胚胎着床的小窗口期间干扰L12介导的信号转导减少胎盘 血管化，诱导自噬，并在以后造成过度炎症的胎盘环境 怀孕了。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，表明了一种失衡。 在L12/R4/R7中，信号可能是致病的。初步数据显示L12/R4信号一过性抑制 子痫前期标志物血管内皮生长因子受体-1(sFlt-1)和胎盘诱导持续性胎盘功能不全 生长因子(PlGF)在妊娠中期几个月后仍保持高水平。R7是否过度激活 对这些发现的贡献，当R4被抑制时仍然不确定。我们的数据强调了 并提供了强有力的证据表明，改变L12介导的信号转导可以诱导持久的 胎盘效应在妊娠后期表现出来。然而，我们对L12是如何， 由胎儿滋养层细胞分泌，通过滋养层细胞和母体细胞上的R4和R7信号。此SC1将 检验L12通过R4和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。来自AIM 1的结果将提供新的 关于R4和R7在胎盘生物学中的作用的科学知识在人类无法获得的时候 通过描述一个健壮的体内模型和特定孕期的胎盘表型。机械论 在AIM 2的体外研究中，将描述胎儿和母体细胞中L12介导的信号转导。

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.