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: 10194564
• 负责人: Madhulika Gupta
• 金额: $ 26.57万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194564
• 关键词: Address; Adult; Affect; Affinity; Age; Amino Acids; Amino Acids Activation; Area; Binding; Binding Proteins; Biological Assay; Biological Availability; 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; IGF1R gene; IGFBP1 gene; Infant; Injury; Insulin; Insulin-Like Growth-Factor Binding Protein 1; Intervention; Knowledge; Late pregnancy; 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; Uterus; Western Blotting; Woman; Work; casein kinase II; design; detection of nutrient; early detection biomarkers; early pregnancy; 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.

宫内生长限制（IUGR）增加了成人围产期并发症的风险 疾病。但是，IUGR基础的病理生理学仍然很了解，没有具体的治疗方法是 缺乏可用的和早期检测的生物标志物。孕产妇循环IGF1通过 影响胎盘功能和低母体IGF1与IUGR相关。产妇的生物利用度 IGF1受到IGF结合蛋白（IGFBP）的强烈影响，尤其是IGFBP1，它结合了 IGF1并降低其生物利用度。另外，IGFBP1的磷酸化显着增加了其结合 对IGF1的亲和力，从而进一步限制IGF1生物活性。 Decidua是母亲的主要来源 怀孕期间的IGFBP1。母体IGFBP1在IUGR发展中的过度磷酸化的作用 是未知的，我们对调节deciDual IGFBP1分泌的分子机制的理解和 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差距 抑制雷帕霉素（MTOR）信号传导和激活氨基酸的定义机械靶标 胎盘不足的反应（AAR）增加了IGFBP1的分泌及其对磷酸化的分泌 特定的丝氨酸残基并增加了早期母体循环中IGFBP1的磷酸化 怀孕与IUGR的发展密切相关。这一假设得到了引人入胜的支持 初步数据，包括i）deciDual MTOR信号传导和IGFBP1含量 IUGR中的磷酸化增加，（ii）MTOR抑制与增加有关 IGFBP1的分泌和磷酸化在人子宫内膜基质细胞和（iii）中的分泌和磷酸化 妊娠早期母体循环中IGFBP1的高磷酸化与 IUGR的发展。我们提出了三个目标。在AIM 1中，我们将确定母亲之间的关系 早期怀孕和IUGR的血清IGFBP1磷酸化。在AIM 2中，我们将确定decidual mtor， CSNK2和AAR活性以及IGFBP1水平以及IUGR中的Decidua和母体血清中的磷酸化水平以及磷酸化。 怀孕晚期。在AIM 3中，我们建议确定MTOR和AAR信号传导的机械作用 使用基因沉默和药理学来调节决结型IGFBP1分泌和磷酸化 人子宫内膜基质细胞系和原发性人类dec骨基质细胞的方法。我们 预计拟议的工作将确定人类发展的基础的新型关键机制 IUGR并建立母体IGFBP1作为IUGR的早期生物标志物的高磷酸化。这项工作将 对研究领域有持续且重大影响，因为它将增加我们对 IUGR，生成新工具以供早期检测 分泌/磷酸化作为IUGR的新干预策略。

项目成果

Mechanistic Target of Rapamycin Complex 1 Signaling Links Hypoxia to Increased IGFBP-1 Phosphorylation in Primary Human Decidualized Endometrial Stromal Cells.

• DOI: 10.3390/biom11091382
• 发表时间: 2021-09-18
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Nandi P;Jang CE;Biggar K;Halari CD;Jansson T;Gupta MB
• 通讯作者: Gupta MB

Increased Insulin-like Growth Factor Binding Protein-1 Phosphorylation in Decidualized Stromal Mesenchymal Cells in Human Intrauterine Growth Restriction Placentas.

人宫内生长受限胎盘蜕膜基质间充质细胞中胰岛素样生长因子结合蛋白 1 磷酸化增加。

• DOI: 10.1369/0022155418772574
• 发表时间: 2018
• 期刊: The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society
• 作者: Singal,SahilS;Nygard,Karen;Gratton,Robert;Jansson,Thomas;Gupta,MadhulikaB
• 通讯作者: Gupta,MadhulikaB