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.

胎儿宫内发育迟缓(IUGR)增加围产期并发症的风险，并易患上成人 疾病。然而，IUGR背后的病理生理机制仍然知之甚少，目前还没有特效的治疗方法。 缺乏可用于早期检测的生物标志物。母体循环IGF1通过以下途径调节胎儿生长 影响胎盘功能和母体IGF1水平低与IUGR相关。母体药物的生物利用度 IGF1受一系列胰岛素样生长因子结合蛋白(IGFBPs)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的磷酸化显著增加了其结合力 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 妊娠期IGFBP1。母体IGFBP1过度磷酸化在胎儿宫内发育迟缓发生中的作用 目前尚不清楚，我们对蜕膜IGFBP1分泌和分泌的分子机制的了解 磷酸化是有限的。在这里，我们将通过检验以下中心假设来解决这一知识缺口 雷帕霉素蜕膜机制靶点信号的抑制和氨基酸的激活 胎盘功能不全反应(AAR)增加IGFBP1的分泌及其磷酸化 早期母体循环中特异的丝氨酸残基和IGFBP1的磷酸化增加 妊娠与胎儿宫内发育迟缓的发生密切相关。这一假设得到了令人信服的支持 初步数据包括：i)蜕膜MTOR信号被抑制和IGFBP1含量 和磷酸化在IUGR中增加，(Ii)MTOR抑制与增加有机械联系 人蜕膜化子宫内膜间质细胞中IGFBP1的分泌和磷酸化 妊娠早期母体循环中IGFBP1的过度磷酸化与 宫内发育迟缓的发展。我们提出了三个目标。在目标1中，我们将确定母体之间的关系 妊娠早期血清IGFBP1磷酸化与胎儿宫内发育迟缓在目标2中，我们将确定分流MTOR， 胎儿宫内发育迟缓蜕膜及母血中CSNK2、AAR活性、IGFBP1水平及磷酸化水平 怀孕晚期。在目标3中，我们建议建立MTOR和AAR信号在 基因沉默和药物作用调节蜕膜IGFBP1的分泌和磷酸化 人子宫内膜间质细胞系和原代人蜕膜间质细胞的研究进展。我们 预期拟议的工作将确定人类发展的一种新的关键机制 并建立母体IGFBP1过度磷酸化作为IUGR早期生物标志物的研究。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，开发新的早期检测工具，为靶向蜕膜IGFBP1铺平道路 分泌/磷酸化作为IUGR的一种新干预策略。

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