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Application of an End-to-End Biomarker Discovery Platform to Identify Target Engagement Markers in Cerebrospinal Fluid by High Resolution Differential Mass Spectrometry
- Source :
- Journal of Proteome Research. 9:1392-1401
- Publication Year :
- 2010
- Publisher :
- American Chemical Society (ACS), 2010.
-
Abstract
- The rapid identification of protein biomarkers in biofluids is important to drug discovery and development. Here, we describe a general proteomic approach for the discovery and identification of proteins that exhibit a statistically significant difference in abundance in cerebrospinal fluid (CSF) before and after pharmacological intervention. This approach, differential mass spectrometry (dMS), is based on the analysis of full scan mass spectrometry data. The dMS workflow does not require complex mixing and pooling strategies, or isotope labeling techniques. Accordingly, clinical samples can be analyzed individually, allowing the use of longitudinal designs and within-subject data analysis in which each subject acts as its own control. As a proof of concept, we performed multifactorial dMS analyses on CSF samples drawn at 6 time points from n = 6 cisterna magna ported (CMP) rhesus monkeys treated with 2 potent gamma secretase inhibitors (GSI) or comparable vehicle in a 3-way crossover study that included a total of 108 individual CSF samples. Using analysis of variance and statistical filtering on the aligned and normalized LC-MS data sets, we detected 26 features that were significantly altered in CSF by drug treatment. Of those 26 features, which belong to 10 distinct isotopic distributions, 20 were identified by MS/MS as 7 peptides from CD99, a cell surface protein. Six features from the remaining 3 isotopic distributions were not identified. A subsequent analysis showed that the relative abundance of these 26 features showed the same temporal profile as the ELISA measured levels of CSF A beta 42 peptide, a known pharmacodynamic marker for gamma-secretase inhibition. These data demonstrate that dMS is a promising approach for the discovery, quantification, and identification of candidate target engagement biomarkers in CSF.
- Subjects :
- Proteomics
Molecular Sequence Data
Computational biology
Cisterna magna
Mass spectrometry
Biochemistry
Mass Spectrometry
Cerebrospinal fluid
Animals
Amino Acid Sequence
Biomarker discovery
Peptide sequence
Analysis of Variance
Amyloid beta-Peptides
Chromatography
Chemistry
Drug discovery
Cerebrospinal Fluid Proteins
General Chemistry
Macaca mulatta
Peptide Fragments
Area Under Curve
Biomarker (medicine)
Amyloid Precursor Protein Secretases
Oligopeptides
Algorithms
Biomarkers
Subjects
Details
- ISSN :
- 15353907 and 15353893
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Journal of Proteome Research
- Accession number :
- edsair.doi.dedup.....13d255981c794105e2811c257bba85e3