Spontaneous Unexplained Preterm Labor with Intact Membrane: Finding Protein Biomarkers through Placenta Proteome (original) (raw)
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An Initial Proteomic Analysis of Human Preterm Labor: Placental Membranes
Journal of Proteome Research, 2006
Human preterm labor (PL) is the single most significant problem in modern Obstetrics and Gynecology, affecting ∼10% of pregnancies worldwide, constituting the leading cause of perinatal mortality and morbidity, and contributing significantly to chronic childhood disease. Currently, our molecular understanding of PL remains staggeringly inadequate to reliably diagnose or rationally intervene in PL events; several molecular alterations have been implicated in PL, but these have proven of limited value as diagnostic/prognostic markers. The majority of PL events remain spontaneous and unpredictable: critical care emergencies. Here, we apply functional proteomics to dissect molecular mechanisms of human PL. Human placental tissue was collected in clearly differentiated cases of preterm and term labor. Highly refined two-dimensional gel electrophoresis (2DE) was used for protein separation, coupled with automated differential gel image analysis to compare the resulting proteomic maps. For this initial study, only the most important protein differences were selected for further analysis, that is, proteins that were unique to one sample, and absent from the other, with 100% reproducibility across the sample population. In total, 11 such proteins were identified by tandem mass spectrometry, falling into three distinct functional classes: structural/cytoskeletal components, ER lumenal proteins with enzymatic or chaperone functions, and proteins with anticoagulant properties. These expression changes form the groundwork for further molecular investigation of this devastating medical condition. This approach therefore holds the potential not only to define the underlying molecular components, but also to identify novel diagnostic tools and targets for rational drug intervention. Keywords: premature birth • obstetrics • 2D-PAGE • LC-MS/MS • child and maternal health • Annexin 4
Journal of Maternal-Fetal and Neonatal Medicine, 2010
Objective. Examination of the amniotic fluid (AF) proteome has been previously attempted to identify useful biomarkers in predicting the outcome of preterm labor (PTL). Isobaric Tag for Relative and Absolute Quantitation (iTRAQ TM ) labeling allows direct ratiometric comparison of relative abundance of identified protein species among multiplexed samples. The purpose of this study was to apply, for the first time, the combination of iTRAQ and tandem mass spectrometry to identify proteins differentially regulated in AF samples of women with spontaneous PTL and intact membranes with and without intra-amniotic infection/inflammation (IAI). Methods. A cross-sectional study was designed and included AF samples from patients with spontaneous PTL and intact membranes in the following groups: (1) patients without IAI who delivered at term (n ¼ 26); (2) patients who delivered preterm without IAI (n ¼ 25); and (3) patients with IAI (n ¼ 24). Proteomic profiling of AF samples was performed using a workflow involving tryptic digestion, iTRAQ labeling and multiplexing, strong cation exchange fractionation, and liquid chromatography tandem mass spectrometry. Twenty-five separate 4-plex samples were prepared and analyzed. Results. Collectively, 123,011 MS 2 spectra were analyzed, and over 25,000 peptides were analyzed by database search (X!Tandem and Mascot), resulting in the identification of 309 unique high-confidence proteins. Analysis of differentially present iTRAQ reporter peaks revealed many proteins that have been previously reported to be associated with preterm delivery with IAI. Importantly, many novel proteins were found to be up-regulated in the AF of patients with PTL and IAI including leukocyte elastase precursor, Thymosin-like 3, and 14-3-3 protein isoforms. Moreover, we observed differential expression of proteins in AF of patients who delivered preterm in the absence of IAI in comparison with those with PTL who delivered at term including Mimecan precursor, latent-transforming growth factor b-binding protein isoform 1L precursor, and Resistin. These findings have been confirmed for Resistin in an independent cohort of samples using ELISA. Gene ontology enrichment The iFirst version of this article published online ahead of print (DOI10.3109/14767050903067386) on 6 August 2009 and contained several errors in text citations and reference numbers. The corrected version is currently displayed online. J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by 183.217.172.138 on 05/20/14 For personal use only.
Frontiers in Physiology, 2020
Introduction: Spontaneous preterm birth (sPTB), which predominantly presents as spontaneous preterm labor (sPTL) or prelabor premature rupture of membranes (PPROM), is a syndrome that accounts for 5-10% of live births annually. The longterm morbidity in surviving preterm infants is significantly higher than that in full-term neonates. The causes of sPTB are complex and not fully understood. Human placenta, the maternal and fetal interface, is an environmental core of fetal intrauterine life, mediates fetal oxygen exchange, nutrient uptake, and waste elimination and functions as an immune-defense organ. In this study, the molecular signature of preterm birth placenta was assessed and compared to full-term placenta by proteomic profiling. Materials and Methods: Four groups of fetal membranes (the amniochorionic membranes), with five cases in each group in the discovery study and 30 cases in each group for validation, were included: groups A: sPTL; B: PPROM; C: full-term birth (FTB); and D: full-term premature rupture of membrane (PROM). Fetal membranes were dissected and used for proteome quantification study. Maxquant and Perseus were used for protein quantitation and statistical analysis. Both fetal membranes and placental villi samples were used to validate proteomic discovery. Results: Proteomics analysis of fetal membranes identified 2,800 proteins across four groups. Sixty-two proteins show statistical differences between the preterm and fullterm groups. Among these differentially expressed proteins are (1) proteins involved in inflammation (HPGD), T cell activation (PTPRC), macrophage activation (CAPG, CD14, and CD163), (2) cell adhesion (ICAM and ITGAM), (3) proteolysis (CTSG, ELANE, and MMP9), (4) antioxidant (MPO), (5) extracellular matrix (ECM) proteins (APMAP, COL4A1, LAMA2, LMNB1, LMNB2, FBLN2, and CSRP1) and (6) metabolism of glycolysis (PKM and ADPGK), fatty acid synthesis (ACOX1 and ACSL3), and energy biosynthesis (ATP6AP1 and CYBB).
Proteomics of the Amniotic Fluid in Assessment of the Placenta. Relevance for Preterm Birth
Placenta, 2008
Proteomics is the study of expressed proteins and has emerged as a complement to genomic research. The major advantage of proteomics over DNA-RNA based technologies is that it more closely relates to phenotype and not the source code. Proteomics thus holds the promise of providing direct insight into the true mechanisms of human disease. Historically, examination of the placenta was the first modality to subclassify pathogenetical entities responsible for preterm birth. Because placenta is a key pathophysiological participant in several major obstetrical syndromes (preterm birth, preeclampsia, intrauterine growth restriction) identification of relevant biomarkers of placental function can profoundly impact on the prediction of fetal outcome and treatment efficacy. Proteomics is a young science and studies that associate proteomic patterns with long-term outcome require follow-up of children up to school age. In the interim, placental pathological footprints of cellular injury can be useful as intermediate outcomes. Furthermore, knowledge of the identity of the dysregulated proteins may provide the necessary insight into novel pathophysiological pathways and unravel possible targets for therapeutic intervention that could not have been envisioned through hypothesis-driven approaches. CLINICAL PROTEOMICS AND MOLECULAR THERANOSTICS AS APPROACHES FOR DISEASE CLASSIFICATION IN OBSTETRICS Proteomics is the field of study that encompasses knowledge of the structure, function and expression of all proteins in the biochemical or biological context of an organism at a given moment. 1,2,3 Since first introduced in the late 1990's, 4 few basic science concepts have evolved as rapidly as proteomics, especially when it became clear after sequencing that the genome itself accounted for only a small percentage of biological processes. In 2005, the March of Dimes Scientific Advisory Committee on Prematurity concluded that it is critical for future research to identify relevant regulatory biomarkers that might impact the prediction of fetal outcome and treatment efficacy. 5 The term biomarker was defined as "an objectively measured characteristic evaluated as an indicator of normal, pathogenic or pharmacologic response of a biological system." Proteomics has all the necessary attributes to identify the combination of
Preterm labor biomarker discovery in serum using 3 proteomic profiling methodologies
American Journal of Obstetrics and Gynecology, 2009
The aim of this study was to identify changes in protein expression in normal pregnancy compared with preterm labor by using 3 proteomic methods. STUDY DESIGN: Serum was collected from 25 nonpregnant (n ϭ 5) and pregnant women at 24 -40 weeks' gestation (n ϭ 20) who had preterm labor resulting in preterm delivery (n ϭ 5), preterm labor with term delivery (n ϭ 5), term labor resulting in delivery (n ϭ 5), or at term with contractions (n ϭ 5). Undepleted serum was used for surface-enhanced laser desorption ionization and immune-depleted serum for matrix-assisted laser desorption ionization and 2-dimensional electrophoresis.
Proteomic profiling of human amnion for preterm birth biomarker discovery
Scientific Reports
Spontaneous preterm birth (PTB) complicates about 12% of pregnancies worldwide, remaining the main cause of neonatal morbidity and mortality. Spontaneous preterm birth PTBs is often caused by microbial-induced preterm labor, mediated by an inflammatory process threatening both maternal and newborn health. In search for novel predictive biomarkers of PTB and preterm prelabor rupture of the membranes (pPROM), and to improve understanding of infection related PTB, we performed an untargeted mass spectrometry discovery study on 51 bioptic mid zone amnion samples from premature babies. A total of 6352 proteins were identified. Bioinformatics analyses revealed a ranked core of 159 proteins maximizing the discrimination between the selected clinical stratification groups allowing to distinguish conditions of absent (FIR 0) from maximal Fetal Inflammatory Response (FIR 3) stratified in function of Maternal Inflammatory Response (MIR) grade. Matrix metallopeptidase-9 (MMP-9) was the top diff...