Dataset Information

Prevention of Proliferative Vitreoretinopathy by Suppression of Phosphatidylinositol 5-Phosphate 4-Kinases.

ABSTRACT: Previous studies have shown that vitreous stimulates degradation of the tumor suppressor protein p53 and that knockdown of phosphatidylinositol 5-phosphate 4-kinases (PI5P4K? and -?) abrogates proliferation of p53-deficient cells. The purpose of this study was to determine whether vitreous stimulated expression of PI5P4K? and -? and whether suppression of PI5P4K? and -? would inhibit vitreous-induced cellular responses and experimental proliferative vitreoretinopathy (PVR).PI5P4K? and -? encoded by PIP4K2A and 2B, respectively, in human ARPE-19 cells were knocked down by stably expressing short hairpin (sh)RNA directed at human PIP4K2A and -2B. In addition, we rescued expression of PI5P4K? and -? by re-expressing mouse PIP4K2A and -2B in the PI5P4K? and -? knocked-down ARPE-19 cells. Expression of PI5P4K? and -? was determined by Western blot and immunofluorescence. The following cellular responses were monitored: cell proliferation, survival, migration, and contraction. Moreover, the cell potential of inducing PVR was examined in a rabbit model of PVR effected by intravitreal cell injection.We found that vitreous enhanced expression of PI5P4K? and -? in RPE cells and that knocking down PI5P4K? and -? abrogated vitreous-stimulated cell proliferation, survival, migration, and contraction. Re-expression of mouse PIP4K? and -? in the human PI5P4K? and -? knocked-down cells recovered the loss of vitreous-induced cell contraction. Importantly, suppression of PI5P4K? and -? abrogated the pathogenesis of PVR induced by intravitreal cell injection in rabbits. Moreover, we revealed that expression of PI5P4K? and -? was abundant in epiretinal membranes from PVR grade C patients.The findings from this study indicate that PI5P4K? and -? could be novel therapeutic targets for the treatment of PVR.

SUBMITTER: Ma G

PROVIDER: S-EPMC4974024 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Prevention of Proliferative Vitreoretinopathy by Suppression of Phosphatidylinositol 5-Phosphate 4-Kinases.

Ma Gaoen G Duan Yajian Y Huang Xionggao X Qian Cynthia X CX Chee Yewlin Y Mukai Shizuo S Cui Jing J Samad Arif A Matsubara Joanne Aiko JA Kazlauskas Andrius A D'Amore Patricia A PA Gu Shuyan S Lei Hetian H

Investigative ophthalmology & visual science 20160701 8

<h4>Purpose</h4>Previous studies have shown that vitreous stimulates degradation of the tumor suppressor protein p53 and that knockdown of phosphatidylinositol 5-phosphate 4-kinases (PI5P4Kα and -β) abrogates proliferation of p53-deficient cells. The purpose of this study was to determine whether vitreous stimulated expression of PI5P4Kα and -β and whether suppression of PI5P4Kα and -β would inhibit vitreous-induced cellular responses and experimental proliferative vitreoretinopathy (PVR).<h4>Me ...[more]

PMID: 27472081

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Project description:Purpose: The development of vitreoretinal scars remains an unsolved challenge in clinical practice and often leads to repeated revision surgery and blindness due to lack of efficient therapy. The aim of this study was to characterize the cellular and molecular environment in vitreoretinal scar tissue from patients with proliferative vitreoretinopathy (PVR) in comparison to membranes of the vitreoretinal junction, in order to subsequently identify potential drug treatment options using bioinformatics techniques. Methods: A total of 23 patients undergoing vitrectomy for retinal detachment due to proliferative vitreoretinopathy (PVR, n = 15), idiopathic macular hole (MH, n = 10) or idiopathic macular pucker (MP, n = 8), were included in this study. Vitreoretinal samples were analysed by RNA sequencing, MS-CyTOF proteomic and by conventional immunohistochemistry. The cellular microenvironment was assessed by bioinformatics cell type enrichment analysis. Drug target screening was performed by using a transcriptome-based drug-repurposing approach using drug-exposure transcriptome data from public available databases. Results: RNA sequencing of vitreoretinal tissue samples showed distinct transcriptional differences of PVR, ERM and ILM samples allowing an accurate clustering according to the tissue types. The cellular microenvironment of PVR membranes was characterized by the enrichment of melanocytes, astrocytes and various immune cell types, such as M2 macrophages. Differential gene expression (DEG) analysis revealed XX up- and XX downregulated genes in PVR compared to ILM. Among them, FN1 (fibronectin1), SPARC (osteonectin) and various collagens were among the most upregulated factors in PVR, contributing to biological processes such as the organization of extracellular structures, the regulation of cell adhesion and the morphogenesis of blood vessels. Finally, we identified 13 drugs that induce a gene expression profile complementary to the PVR signature and thus represent potential therapeutic options for PVR, including aminocaproic acid and various topoisomerase 2A inhibitors such as doxorubicin, etoposide and mitoxantrone. Conclusion: The present study reveals significant differences in the transcriptional signature of vitreoretinal scar tissue including PVR, MP and ILM tissue. Among a plethora of differentially expressed genes, FN1 and SPARC appeared to be central mediators underlying PVR development. Based on the transcriptome analyses, aminocaproic acid and topoisomerase-2 inhibitors, such as doxorubicin, etoposide and mitoxantrone, were identified as compatible drugs for the treatment of PVR.

Dataset Information

Prevention of Proliferative Vitreoretinopathy by Suppression of Phosphatidylinositol 5-Phosphate 4-Kinases.

Publications

Prevention of Proliferative Vitreoretinopathy by Suppression of Phosphatidylinositol 5-Phosphate 4-Kinases.

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