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Natarajan Perumal, Sebastian Funke, Wolters Dominik, Norbert Pfeiffer, Franz H Grus; In-depth protein profiling and identification of tear fluid biomarkers in different subgroups of dry eye disease: Proline-Rich Protein 4 (PRR4) as a potential biomarker for aqueous-deficient dry eye syndrome. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2002.
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Our previous studies demonstrated that the truncated form of PRR4 is down regulated in the tears of dry eye patients. Therefore, we have extensively characterized PRR4 as a highly abundant protein in healthy human tears. In the study presented herein, our aim was to examine the profiles and distribution of characterized PRR4 and other proteins in the different subgroups of dry eye patients.
Twenty healthy subjects (CTRL) and 60 patients with dry eye were recruited. Dry eye patients were subdivided into aqueous-deficient dry eye (DRYaq: N=20), lipid-deficient dry eye (DRYlip: N=20), and a combination of the two (DRYaqlip: N=20). Tear samples were collected using Schirmer's strips. Label-free quantitative proteomics based on one-dimensional gel electrophoresis combined with the LC-ESI-LTQ-Orbitrap MS system was employed to identify candidate biomarkers from the tear samples. Subsequently, the identified candidate biomarkers were validated by utilizing a targeted data acquisition approach based on in-solution digestion combined with the LC-ESI-LTQ-Orbitrap-MS system.
PRR4 was found to be significantly down-regulated in both DRYaq and DRYaqlip groups. The major regulation levels of PRR4 reflect the aqueous secretion deficiency by lacrimal gland and thus, it is highly regarded as a potential biomarker for DRYaq. Conversely, Ig alpha-1 chain C region and 14-3-3 zeta/delta proteins were down-regulated in both DRYlip and DRYaqlip groups. Commonly reported proteins such as lipocalin-1, lactotransferrin and prolactin-inducible proteins were found to be down-regulated across all groups of dry eye disease. Up-regulation of inflammatory proteins (e.g. S100-A8 and S100-A9) and serotransferin are associated with DRYaqlip.
The findings of this study demonstrate that the different groups of dry eye are associated with specific alterations in the tear proteome, and substantiate PRR4 as a potential biomarker for the aqueous-deficient dry eye subgroup. These results, when extrapolated to clinical application, can give invaluable hints on advanced therapies and are of great importance for the treatment of the specific dry eye disease.
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