Decidual nutrient sensing and IGFBP-1 phosphorylation in placental insufficiency

胎盘功能不全中的蜕膜营养感应和 IGFBP-1 磷酸化

• 批准号: 9402772
• 负责人: Madhulika Gupta
• 金额: $ 28.51万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9402772
• 关键词: Address; Adult; Affect; Affinity; Age; Amino Acids; Amino Acids Activation; Area; Binding; Binding Proteins; Biological Assay; Biological Availability; Biological Markers; Blood Circulation; Cardiovascular Diseases; Cell Line; Cells; Childhood; Data; Decidua; Decidual Cell Reactions; Development; Diabetes Mellitus; Disease; Early Diagnosis; Endometrial Stromal Cell; Endometrium; Enzyme-Linked Immunosorbent Assay; FRAP1 gene; Family; Fetal Growth; Fetal Growth Retardation; Fetus; Functional disorder; Gene Silencing; Gestational Age; Growth; Growth Factor; Hormones; Human; Hypoxia; IGFBP1 gene; Infant; Injury; Insulin; Insulin-Like Growth-Factor Binding Protein 1; Intervention; Knowledge; Left; Life; Link; Low Birth Weight Infant; Mass Spectrum Analysis; Mediating; Molecular; Mothers; Nested Case-Control Study; Obesity; Outcome; Oxygen; Performance; Pharmacology; Phosphorylation; Phosphorylation Site; Placental Insufficiency; Pregnancy; Pregnancy Complications; Research; Research Design; Risk; Role; Sampling; Second Pregnancy Trimester; Serine; Serum; Signal Transduction; Site; Small Interfering RNA; Source; Stromal Cells; System; Testing; Western Blotting; Woman; Work; casein kinase II; design; detection of nutrient; early detection biomarkers; established cell line; fetal; maternal serum; novel; novel diagnostics; nutrient deprivation; perinatal complications; public health relevance; response; tool; trophoblast

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.

宫内生长受限（IUGR）会增加围产期并发症的风险，并容易导致成人 疾病。然而，对于 IUGR 的病理生理学仍然知之甚少，没有具体的治疗方法 可用且缺乏用于早期检测的生物标志物。母体循环 IGF1 通过以下方式调节胎儿生长 影响胎盘功能，母体 IGF1 低与 IUGR 相关。母体生物利用度 IGF1 受到 IGF 结合蛋白 (IGFBP) 家族的强烈影响，特别是 IGFBP1，它结合 IGF1 并降低其生物利用度。此外，IGFBP1 的磷酸化显着增加其结合 与 IGF1 的亲和力，从而进一步限制 IGF1 的生物活性。蜕膜是母体的主要来源 怀孕期间的 IGFBP1。母体 IGFBP1 过度磷酸化在 IUGR 发展中的作用 尚不清楚，我们对调节蜕膜 IGFBP1 分泌的分子机制的理解和 磷酸化作用有限。在这里，我们将通过测试以下中心假设来解决这一知识差距： 抑制雷帕霉素蜕膜机制靶点 (MTOR) 信号传导和氨基酸激活 胎盘功能不全中的反应（AAR）增加了 IGFBP1 的分泌及其磷酸化 特定的丝氨酸残基，并增加早期母体循环中 IGFBP1 的磷酸化 妊娠与 IUGR 的发生密切相关。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 IGFBP1 含量的证明 IUGR 中磷酸化增加，(ii) MTOR 抑制在机制上与增加有关 蜕膜化人子宫内膜基质细胞中 IGFBP1 的分泌和磷酸化以及 (iii) 妊娠早期母体循环中 IGFBP1 的过度磷酸化与 IUGR 的发展。我们提出三个目标。在目标 1 中，我们将确定母亲之间的关系 妊娠早期血清 IGFBP1 磷酸化和 IUGR。在目标 2 中，我们将确定蜕膜 MTOR， IUGR 中蜕膜和母体血清中 CSNK2 和 AAR 活性以及 IGFBP1 水平和磷酸化 怀孕晚期。在目标 3 中，我们建议建立 MTOR 和 AAR 信号传导在 利用基因沉默和药理学调节蜕膜 IGFBP1 分泌和磷酸化 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 预计拟议的工作将确定人类发展背后的一种新的关键机制 IUGR 并将母体 IGFBP1 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而重大的影响，因为它将增加我们对 IUGR，生成用于早期检测的新工具，并为针对蜕膜 IGFBP1 铺平道路 分泌/磷酸化作为 IUGR 的新干预策略。