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Project description:Down syndrome (DS), a genetic condition leading to intellectual disability, is characterized by triplication of human chromosome 21. Neuropathological hallmarks of DS include abnormal central nervous system development that manifests during gestation and extends throughout life. As a result, newborns and adults with DS exhibit cognitive and motor deficits and fail to meet typical developmental and lack independent life skills. As of summer 2020, 13 pharmacological interventions have been tested with little evidence of success in improving cognition in humans with DS. Potential reasons for this failure may be related to the fact that these therapeutic interventions were carried out too late, and not during the prenatal and early postnatal critical periods for brain development. To date, no prenatal treatment studies have been reported in pregnant women carrying fetuses with T21. A limited number of prenatal treatment studies using fluoxetine, maternal choline supplementation and the neuroprotective peptides NAP and SAL have been described using the Ts65Dn mouse model of DS. In our previous studies, we integrated gene expression data from nine different cellular and tissue sources in both humans with DS and mouse models to identify common dysregulated signaling pathways and cellular processes. We demonstrated that pathway abnormalities associated with DS were the result of gene-dosage specific effects and the consequence of a global stress response with activation of compensatory mechanisms. To counteract these genome-wide abnormalities, we used the Connectivity Map database (www.broadinstitute.org/CMap) to discover molecules that could be repurposed to rescue the transcriptome and promote more typical brain development in individuals with DS. One of the molecules that had the most consistent negative scores (hence, negating the dysregulated gene expression signatures in DS) across tissues and species was apigenin (4’, 5, 7-trihydroxyflavone). Here, we hypothesized that prenatal treatment with apigenin would partly rescue the global gene expression dysregulation to improve neurogenesis and postnatal cognitive outcomes in DS. In the current study, we used a human in vitro cell model (amniocytes derived from live fetuses with Trisomy 21 and euploid fetuses) and the Ts1Cje mouse model of DS to evaluate the effects of apigenin as a potential therpay for prenatal brain defects and postnatal cognitive outcome in DS. We demonstrated that apigenin is a safe treatment that can rescue oxidative stress and total antioxidant capacity imbalance in human amniocytes from fetuses with T21. It also improved several postnatal behavioral deficits in the Ts1Cje mouse model. We also showed that apigenin achieves its therapeutic action by triggering the expression of neurogenic genes, suppressing inflammation via inhibiting NFκB and by reducing the production of pro-inflammatory cytokines, while promoting the production of anti-inflammatory cytokines, angiogenic and neurotrophic factors.
2020-09-23 | GSE158377 | GEO
Project description:Down syndrome (DS), a genetic condition leading to intellectual disability, is characterized by triplication of human chromosome 21. Neuropathological hallmarks of DS include abnormal central nervous system development that manifests during gestation and extends throughout life. As a result, newborns and adults with DS exhibit cognitive and motor deficits and fail to meet typical developmental and lack independent life skills. In the last two decades, a number of preclinical treatment studies showed beneficial effects in the Ts65Dn mouse model. As of summer 2020, 13 pharmacological interventions have been tested with little evidence of success in humans with DS. Potential reasons for this failure may be related to the fact that these therapeutic interventions were carried out too late, and not during the prenatal and early postnatal critical periods for brain development. To date, no prenatal treatment studies have been reported in pregnant women carrying fetuses with T21. A limited number of prenatal treatment studies using fluoxetine, maternal choline supplementation and the neuroprotective peptides NAP and SAL have been described using the Ts65Dn mouse model of DS. In our previous studies, we integrated gene expression data from nine different cellular and tissue sources in both humans with DS and mouse models to identify common dysregulated signaling pathways and cellular processes. We demonstrated that pathway abnormalities associated with DS were the result of gene-dosage specific effects and the consequence of a global stress response with activation of compensatory mechanisms. To counteract these genome-wide abnormalities, we used the Connectivity Map database (www.broadinstitute.org/CMap) to discover molecules that could be repurposed to rescue the transcriptome and promote more typical brain development in individuals with DS. One of the molecules that had the most consistent negative scores (hence, negating the dysregulated gene expression signatures in DS) across tissues and species was apigenin (4’, 5, 7-trihydroxyflavone). Here, we hypothesized that prenatal treatment with apigenin would partly rescue the global gene expression dysregulation to improve neurogenesis and postnatal cognitive outcomes in DS. In the current study, we used a human in vitro cell model (amniocytes derived from live fetuses with Trisomy 21 and euploid fetuses) and the Ts1Cje mouse model of DS to evaluate the effects of apigenin as a potential therpay for prenatal brain defects and postnatal cognitive outcome in DS. We demonstrated that apigenin is a safe treatment that can rescue oxidative stress and total antioxidant capacity imbalance in human amniocytes from fetuses with T21. It also improved several postnatal behavioral deficits in the Ts1Cje mouse model. We also showed that apigenin achieves its therapeutic action by triggering the expression of neurogenic genes, suppressing inflammation via inhibiting NFκB and by reducing the production of pro-inflammatory cytokines, while promoting the production of anti-inflammatory cytokines, angiogenic and neurotrophic factors.
2020-09-23 | GSE158376 | GEO
Project description:Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model
| PRJNA665042 | ENA
Project description:Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model [Mouse]
| PRJNA665036 | ENA
Project description:Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model [Human]
| PRJNA665046 | ENA
Project description:Congenital development disorders with variable severity occur in trisomy 21. However, how these phenotypic abnormalities develop with variations remains elusive. We hypothesize that the difference in euploidy gene expression variation among trisomy 21 tissues are perturbed by the presence of an extra copy of chromosome 21 and this may contribute to the phenotypic variations in Down syndrome. Experiment Overall Design: We used DNA microarray to measure the differences in gene expression variance (representing variation) between four human trisomy 21 amniocytes and six human euploid amniocytes.
2008-04-03 | E-GEOD-10758 | biostudies-arrayexpress
Project description:BackgroundMolecular size determination of circulating free fetal DNA in maternal plasma is an important detection method for noninvasive prenatal testing (NIPT). The fetal DNA molecule is the primary factor determining the overall performance of NIPT and its clinical interpretation. The proportion of cell-free fetal DNA molecules is expressed as the fetal DNA fraction in the plasma of pregnant women.MethodsWe proposed an effective method to deduce fetal chromosomal aneuploidy based on the proportion of a certain range of DNA fragment lengths from maternal plasma. We gradually narrowed the range of the upper and lower boundary via a traversing algorithm.ResultsWe explored the optimal range of the upper and lower boundary by using size-based DNA fragment length. Using this range, the accuracy of the sensitivity and specificity could be improved by up to 100% for detecting the three most common autosomal aneuploidies, namely trisomy 13, trisomy 18, trisomy 21 in the sample set.ConclusionsNumerical experiments demonstrate that our method is effective and efficient. The program is available upon request.
| S-EPMC6461288 | biostudies-literature
Project description:Down syndrome (DS), also known as trisomy 21 (T21), is the most common human chromosomal anomaly. Although DS can affect many organ systems, lung and heart disease are the leading causes of death. An abundance of existing data suggests that lung abnormalities originate postnatally in DS. However, a single report of branching insufficiency in DS has inferred a potential prenatal origin. The histology of T21 fetal lungs (n = 15) was assessed by an experienced pathologist. Spatial differences in cellular phenotypes were examined using immunohistochemistry (IHC). Comprehensive gene expression in prenatal T21 lungs (n = 19), and age-matched controls (n = 19), was performed using high-throughput RNA sequencing (RNAseq) and validated by RT-qPCR. Histopathological abnormalities were observed in approximately half of T21 prenatal lung samples analyzed, which included dilated terminal airways/acinar tubules, dilated lymphatics, and arterial wall thickening. IHC for Ki67 revealed significant reductions in epithelial and mesenchymal cell proliferation, predominantly in tissues displaying pathology. IHC demonstrated that airway smooth muscle was reduced and discontinuous in the proximal airway in conjunction with reduced SOX2. RNAseq identified 118 genes significantly dysregulated (FDR < 0.05) in T21 lung when unadjusted and 316 genes when adjusted for age. Ontology analysis showed that IFN pathway genes were appreciably upregulated, whereas complement and coagulation cascades and extracellular matrix pathway genes were downregulated. RT-qPCR confirmed the changes in genes associated with these pathways in prenatal T21 lungs. Our data demonstrate that specific histological, cellular, and molecular abnormalities occur prenatally in different compartments of human T21 lung, which could be representative of premature stage progression. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
| S-EPMC9109699 | biostudies-literature
Project description:A universal biomarker panel with the potential to predict high-risk pregnancies or adverse pregnancy outcome does not exist. Transcriptome analysis is a powerful tool to capture differentially expressed genes (DEG), which can be used as biomarker-diagnostic-predictive tool for various conditions in prenatal setting. In search of biomarker set for predicting high-risk pregnancies, we performed global expression profiling to find DEG in Ts21. Subsequently, we performed targeted validation and diagnostic performance evaluation on a larger group of case and control samples. Initially, transcriptomic profiles of 10 cultivated amniocyte samples with Ts21 and 9 with normal euploid constitution were determined using expression microarrays. Datasets from Ts21 transcriptomic studies from GEO repository were incorporated. DEG were discovered using linear regression modelling and validated using RT-PCR quantification on an independent sample of 16 cases with Ts21 and 32 controls. The classification performance of Ts21 status based on expression profiling was performed using supervised machine learning algorithm and evaluated using a leave-one-out cross validation approach. Global gene expression profiling has revealed significant expression changes between normal and Ts21 samples, which in combination with data from previously performed Ts21 transcriptomic studies, were used to generate a multi-gene biomarker for Ts21, comprising of 9 gene expression profiles. In addition to biomarker's high performance in discriminating samples from global expression profiling, we were also able to show its discriminatory performance on a larger sample set 2, validated using RT-PCR experiment (AUC=0.97), while its performance on data from previously published studies reached discriminatory AUC values of 1.00. Our results show that transcriptomic changes might potentially be used to discriminate trisomy of chromosome 21 in the prenatal setting. As expressional alterations reflect both, causal and reactive cellular mechanisms, transcriptomic changes may thus have future potential in the diagnosis of a wide array of heterogeneous diseases that result from genetic disturbances.
| S-EPMC3774664 | biostudies-literature
Project description:The trials performed worldwide toward noninvasive prenatal diagnosis (NIPD) of Down's syndrome (or trisomy 21) have shown the commercial and medical potential of NIPD compared to the currently used invasive prenatal diagnostic procedures. Extensive investigation of methylation differences between the mother and the fetus has led to the identification of differentially methylated regions (DMRs). In this study, we present a strategy using the methylated DNA immunoprecipitation (MeDiP) methodology in combination with real-time quantitative PCR (qPCR) to achieve fetal chromosome dosage assessment, which can be performed noninvasively through the analysis of fetal-specific DMRs. We achieved noninvasive prenatal detection of trisomy 21 by determining the methylation ratio of normal and trisomy 21 cases for each tested fetal-specific DMR present in maternal peripheral blood, followed by further statistical analysis. The application of this fetal-specific methylation ratio approach provided correct diagnosis of 14 trisomy 21 and 26 normal cases.
| S-EPMC3977039 | biostudies-literature