Decidual nutrient sensing and IGFBP-1 phosphorylation in placental insufficiency

胎儿宫内生长受限（IUGR）增加了围生期并发症的风险， 疾病然而，IUGR的病理生理机制仍然知之甚少， 缺乏早期检测的生物标志物。母体循环IGF 1通过以下途径调节胎儿生长： 影响胎盘功能和低母体IGF 1与IUGR相关。母体药物的生物利用度 IGF 1受IGF结合蛋白（IGFBP）家族，特别是IGFBP 1的强烈影响，IGFBP 1结合 IGF 1，降低其生物利用度。此外，IGFBP 1的磷酸化显著增加了其结合 对IGF 1的亲和力，从而进一步限制IGF 1的生物活性。蜕膜是母体的主要来源， IGFBP 1在怀孕期间母体IGFBP 1过度磷酸化在IUGR发生中的作用 目前尚不清楚，我们对调节蜕膜IGFBP 1分泌的分子机制的理解， 磷酸化是有限的。在此，我们将通过检验中心假设来解决这一知识缺口， 抑制雷帕霉素（MTOR）信号传导的蜕膜机制靶点和激活氨基酸 在胎盘功能不全中的AAR增加IGFBP 1的分泌及其在胎盘上的磷酸化， 特异性丝氨酸残基和IGFBP 1磷酸化增加， 怀孕与IUGR的发展密切相关。这一假设得到了令人信服的支持， 初步数据，包括i）蜕膜MTOR信号传导被抑制和IGFBP 1含量 和磷酸化增加IUGR，（ii）MTOR抑制机制与增加 IGFBP 1在蜕膜化的人子宫内膜基质细胞中的分泌和磷酸化，和（iii） 妊娠早期母体循环中IGFBP 1的过度磷酸化与 IUGR的发展。我们提出三个目标。在目标1中，我们将确定产妇之间的关系， 妊娠早期和IUGR中血清IGFBP 1磷酸化。在目标2中，我们将确定蜕膜MTOR， IUGR孕妇蜕膜和母体血清中CSNK 2和AAR活性、IGFBP 1水平和磷酸化 怀孕晚期。在目标3中，我们提出建立MTOR和AAR信号传导在 使用基因沉默和药理学调节蜕膜IGFBP 1分泌和磷酸化 在人子宫内膜基质细胞系和原代人蜕膜基质细胞中的方法。我们 我预计，拟议的工作将确定一个新的关键机制的发展，人类 IUGR和建立母体IGFBP 1的过度磷酸化作为IUGR的早期生物标志物。这项工作将 对研究领域产生持续和重大的影响，因为它将增加我们对 IUGR，产生早期检测的新工具，并为靶向蜕膜IGFBP 1铺平道路 分泌/磷酸化作为IUGR的新干预策略。

Intrauterine growth restriction (IUGR) increases the risk for perinatal complications and predisposes for adult disease. However, the pathophysiology underlying IUGR remains poorly understood, no specific treatment is available and biomarkers for early detection are lacking. Maternal circulating IGF1 regulates fetal growth by affecting placental function and low maternal IGF1 is associated with IUGR. The bioavailability of maternal IGF1 is strongly influenced by a family of IGF binding proteins (IGFBPs), in particular IGFBP1, which binds IGF1 and decreases its bioavailability. In addition, phosphorylation of IGFBP1 markedly increases its binding affinity for IGF1, thereby limiting IGF1 bioactivity further. The decidua is the primary source of maternal IGFBP1 during pregnancy. The role of hyperphosphorylation of maternal IGFBP1 in the development of IUGR is unknown and our understanding of the molecular mechanisms regulating decidual IGFBP1 secretion and phosphorylation is limited. Herein, we will address this gap of knowledge by testing the central hypothesis that inhibition of decidual mechanistic target of rapamycin (MTOR) signaling and activation of the amino acid response (AAR) in placental insufficiency increases the secretion of IGFBP1 and its phosphorylation on specific serine residues and that increased phosphorylation of IGFBP1 in the maternal circulation in early pregnancy is strongly associated with the development of IUGR. This hypothesis is supported by compelling preliminary data including the demonstration that i) decidual MTOR signaling is inhibited and IGFBP1 content and phosphorylation are increased in IUGR, (ii) MTOR inhibition is mechanistically linked to increased secretion and phosphorylation of IGFBP1 in decidualized human endometrial stromal cells and (iii) hyperphosphorylation of IGFBP1 in the maternal circulation in early pregnancy is associated with the development of IUGR. We propose three aims. In Aim 1 we will determine the relationship between maternal serum IGFBP1 phosphorylation in early pregnancy and IUGR. In Aim 2 we will determine decidual MTOR, CSNK2 and AAR activity and IGFBP1 levels and phosphorylation in decidua and maternal serum in IUGR in late pregnancy. In Aim 3 we propose to establish the mechanistic role of MTOR and AAR signaling in regulating decidual IGFBP1 secretion and phosphorylation using gene silencing and pharmacological approaches in human endometrial stromal cell lines and in primary human decidual stromal cells. We anticipate that the proposed work will identify a novel key mechanism underlying the development of human IUGR and establish hyperphosphorylation of maternal IGFBP1 as an early biomarker of IUGR. This work will have a sustained and significant impact on the research area because it will increase our understanding of IUGR, generate new tools for early detection and pave the way for targeting decidual IGFBP1 secretion/phosphorylation as a new intervention strategy in IUGR.