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）增加围产期并发症和成人易感性的风险