Functional Network Profiles In Arsacs Disclosed By Aptamer-Based Proteomic Technology
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PROVIDER: PRJNA680713 | ENA |
REPOSITORIES: ENA
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Project description:Although the genetic basis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) has been uncovered, the cellular and molecular mechanisms characterizing this rare neurodegenerative disease are still under investigation, and no cure has yet been developed. In this study, we analyzed proteomics data obtained using the SomaLogic technology, comparing cell lysates from ARSACS patients and from a SACS KO SH-SY5Y neuroblastoma cell model. Single-stranded deoxyoligonucleotides, selected in vitro from large random libraries, bound and quantified molecular targets related to the neuroinflammation signaling pathway and to neuronal development. Changes in protein levels were further analyzed by bioinformatics and network approaches to identify biomarkers of ARSACS and functional pathways impaired in the disease. We identified novel significantly dysregulated biological processes related to neuroinflammation, synaptogenesis and engulfment of cells in patients and in KO cells compared with controls. Among the differential expressed proteins found in this work, we identified several proteins encoded by genes already known to be mutated in other forms of neurodegeneration. This finding suggests that common dysfunctional networks could be therapeutic targets for future investigations.
2020-11-26 | GSE162132 | GEO
Project description:Although the genetic basis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) has been uncovered, our poor understanding of disease mechanisms requires new light on functional pathways and modifying factors to improve early diagnostic strategies and offer alternative treatment options in a rare condition with no cure. Investigation of the pathologic state combining disease models and quantitative omic approach might improve biomarkers discovery with possible implications in patients' diagnoses. In this study, we analyzed proteomics data obtained using the SomaLogic technology, comparing cell lysates from ARSACS patients and from a SACS KO SH-SY5Y neuroblastoma cell model. Single-stranded deoxyoligonucleotides, selected in vitro from large random libraries, bound and quantified molecular targets related to the neuroinflammation signaling pathway and to neuronal development. Changes in protein levels were further analyzed by bioinformatics and network approaches to identify biomarkers of ARSACS and functional pathways impaired in the disease. We identified novel significantly dysregulated biological processes related to neuroinflammation, synaptogenesis, and engulfment of cells in patients and in KO cells compared with controls. Among the differential expressed proteins found in this work, we identified several proteins encoded by genes already known to be mutated in other forms of neurodegeneration. This finding suggests that common dysfunctional networks could be therapeutic targets for future investigations.
| S-EPMC7873355 | biostudies-literature
Project description:Ngo D, Sinha S, Shen D, Kuhn E, Keyes M, Shi X, Benson M, O'Sullivan J, Keshishian H, Farrell L, Fifer MA, Vasan RS, Sabatine M, Larson MG, Carr SA, Wang TJ, Gerszten RE. Circulation 2016. Emerging proteomic technologies are beginning to permit the systematic characterization of human plasma samples. DNA-aptamer based technologies may address limitations of existing proteomic techniques, including low sample throughput, which have prevented proteomic analyses of large cohorts. We applied an aptamer-based proteomic technology that measures 1,129 proteins to identify potential novel biomarkers of cardiovascular disease. We found very early markers of myocardial injury in a robust, clinically-relevant perturbational model of planned myocardial injury, patients undergoing septal ablation for hypertrophic cardiomyopathy. We then tested whether the platform could detect novel associations between proteins and cardiovascular risk factors in individuals without overt cardiovascular disease using archived samples from the Framingham Heart Study. Further, we developed a new workflow integrating DNA-based immunoaffinity with mass spectrometry to analytically validate the specificity of aptamer findings. Our results highlight an emerging proteomics tool capable of profiling over one thousand low abundance analytes with high sensitivity and high precision, applicable both to well-phenotyped perturbational studies as well as large human cohorts.
2016-07-14 | MSV000079908 | MassIVE
Project description:BackgroundThe interrogation of proteomes ("proteomics") in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology and medicine.Methodology/principal findingsWe present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 µL of serum or plasma). Our current assay measures 813 proteins with low limits of detection (1 pM median), 7 logs of overall dynamic range (~100 fM-1 µM), and 5% median coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding signature of DNA aptamer concentrations, which is quantified on a DNA microarray. Our assay takes advantage of the dual nature of aptamers as both folded protein-binding entities with defined shapes and unique nucleotide sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to rapidly discover unique protein signatures characteristic of various disease states.Conclusions/significanceWe describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine.
| S-EPMC3000457 | biostudies-literature
Project description:The experiments were carried out to map the ligand binding landscape of various DNA and RNA duplexed aptamer families. Duplexed Aptamer (DA) constructs were engineered from (i) natural and synthetic DNA and RNA aptamers and (i) synthetic oligonucleotide aptamer-complementary elements synthesized on custom DNA microarrays. The aptamers tested consist of the ATP DNA aptamer, the ATP RNA aptamer, the cocaine DNA aptamer, the human alpha-thrombin DNA aptamer, and the natural add riboswitch aptamer from the pathogenic bacteria Vibrio vulnificus. Each duplexed aptamer family consists of 1000's of synthetic constructs, each formed by hybridizing the aptamer with an aptamer-complementary element (ACE) - here, ACEs consisted of various DNA oligonucleotides synthesized as a custom DNA microarray.
2017-12-20 | E-MTAB-6375 | biostudies-arrayexpress
Project description:The experiments were carried out to map the ligand binding landscape of various DNA and RNA duplexed aptamer families. Duplexed Aptamer (DA) constructs were engineered from (i) natural and synthetic DNA and RNA aptamers and (i) synthetic oligonucleotide aptamer-complementary elements synthesized on custom DNA microarrays. The aptamers tested consist of the ATP DNA aptamer, the ATP RNA aptamer, the cocaine DNA aptamer, the human alpha-thrombin DNA aptamer, and the natural add riboswitch aptamer from the pathogenic bacteria Vibrio vulnificus. Each duplexed aptamer family consists of 1000's of synthetic constructs, each formed by hybridizing the aptamer with an aptamer-complementary element (ACE) - here, ACEs consisted of various DNA oligonucleotides synthesized as a custom DNA microarray.
2017-12-20 | E-MTAB-6377 | biostudies-arrayexpress
Project description:The experiments were carried out to map the ligand binding landscape of various DNA and RNA duplexed aptamer families. Duplexed Aptamer (DA) constructs were engineered from (i) natural and synthetic DNA and RNA aptamers and (i) synthetic oligonucleotide aptamer-complementary elements synthesized on custom DNA microarrays. The aptamers tested consist of the ATP DNA aptamer, the ATP RNA aptamer, the cocaine DNA aptamer, the human alpha-thrombin DNA aptamer, and the natural add riboswitch aptamer from the pathogenic bacteria Vibrio vulnificus. Each duplexed aptamer family consists of 1000's of synthetic constructs, each formed by hybridizing the aptamer with an aptamer-complementary element (ACE) - here, ACEs consisted of various DNA oligonucleotides synthesized as a custom DNA microarray.
2017-12-20 | E-MTAB-6376 | biostudies-arrayexpress
Project description:The experiments were carried out to map the ligand binding landscape of various DNA and RNA duplexed aptamer families. Duplexed Aptamer (DA) constructs were engineered from (i) natural and synthetic DNA and RNA aptamers and (i) synthetic oligonucleotide aptamer-complementary elements synthesized on custom DNA microarrays. The aptamers tested consist of the ATP DNA aptamer, the ATP RNA aptamer, the cocaine DNA aptamer, the human alpha-thrombin DNA aptamer, and the natural add riboswitch aptamer from the pathogenic bacteria Vibrio vulnificus. Each duplexed aptamer family consists of 1000's of synthetic constructs, each formed by hybridizing the aptamer with an aptamer-complementary element (ACE) - here, ACEs consisted of various DNA oligonucleotides synthesized as a custom DNA microarray.
2017-12-20 | E-MTAB-6374 | biostudies-arrayexpress
Project description:PurposeTo explore top-ranked plasma proteins related to neovascular age-related macular degeneration (AMD) and geographic atrophy (GA), and explore pathways related to neovascular AMD and GA.MethodsWe conducted a pilot study of patients with neovascular AMD (n = 10), GA (n = 10), and age-matched cataract controls (n = 10) who were recruited into an AMD registry. We measured 4001 proteins in ethylenediaminetetraacetic acid plasma samples using an aptamer-based proteomic technology. Relative concentrations of each of 4001 proteins were log (base 2) transformed and compared between cases of neovascular AMD and GA versus controls using linear regression. Pathway analysis was conducted using pathways downloaded from Reactome.ResultsIn this pilot study, higher levels of vinculin and lower levels of CD177 were found in patients with neovascular AMD compared with controls. Neuregulin-4 was higher and soluble intercellular adhesion molecule-1 was lower in patients with GA compared with controls. For neovascular AMD, cargo trafficking to the periciliary membrane, fibroblast growth factor receptor 3b ligand binding and activation, and vascular endothelial growth factor-related pathways were in the top ranked pathways. The top-ranked pathways for GA included several related to ErbB4 signaling.ConclusionsWe found different proteins and different pathways associated with neovascular AMD and GA. Vinculin and some of the top-ranked pathways have been previously associated with AMD, whereas others have not been described.Translational relevanceBiomarkers identified in plasma likely reflect systemic alterations in protein expression and may improve our understanding of the mechanisms leading to AMD.
| S-EPMC6348995 | biostudies-literature
Project description:Purpose: There is a need to identify new biomarkers of radiation exposure both for use in the development of biodosimetry blood diagnostics for radiation exposure and for clinical use as markers of radiation injury. In the current study, a novel high-throughput proteomics screening approach was used to identify proteomic markers of radiation exposure in the plasma of total body irradiated mice. A subset panel of significantly altered proteins was selected to build predictive models of radiation exposure and received radiation dose useful for population screening in a future radiological or nuclear event. Methods: Female C57BL6 Mice of 8-14 weeks of age received a single total body irradiation (TBI) dose of 2, 3.5, 8 Gy or sham radiation and plasma was collected by cardiac puncture at days 1, 3, and 7 post-exposure. Plasma was then screened using the aptamer-based SOMAscan proteomic assay technology, for changes in expression of 1,310 protein analytes. A subset panel of protein biomarkers which demonstrated significant changes (p < 0.05) in expression following radiation exposure were used to build predictive models of radiation exposure and radiation dose. Results: Detectable values were obtained for all 1,310 proteins included in the SOMAscan assay. For the Control vs. Radiation model, the top predictive proteins were immunoglobulin heavy constant mu (IGHM), mitogen-activated protein kinase 14 (MAPK14), ectodysplasin A2 receptor (EDA2R) and solute carrier family 25 member 18 (SLC25A18). For the Control vs. Dose model, the top predictive proteins were cyclin dependent kinase 2/cyclin A2 (CDK2. CCNA2), E-selectin (SELE), BCL2 associated agonist of cell death (BAD) and SLC25A18. Following model validation with a training set of samples, both models tested with a new sample cohort had overall predictive accuracies of 85% and 73% for the Control vs. Radiation and Control vs. Dose models respectively. Conclusion: The SOMAscan proteomics platform is a useful screening tool to evaluate changes in biomarker expression. In our study we were able to identify a novel panel of radiation responsive proteins useful for predicting whether an animal had received a radiation exposure and to what dose they had received. Such diagnostic tools are needed for future medical management of radiation exposures.
| S-EPMC8110031 | biostudies-literature