Microarray Analysis of Gene Expression in Fibrovascular Membranes Excised From Patients With Proliferative Diabetic Retinopathy

Ishikawa, Keijiro; Yoshida, Shigeo; Kobayashi, Yoshiyuki; Zhou, Yedi; Nakama, Takahito; Nakao, Shintaro; Sassa, Yukio; Oshima, Yuji; Niiro, Hiroaki; Akashi, Koichi; Kono, Toshihiro; Ishibashi, Tatsuro

doi:10.1167/iovs.14-15589

Cited by 59 publications

(50 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several laboratories including ours have demonstrated a higher expression of periostin (POSTN) in the fibrovascular membranes (FVMs) of patients with PDR than in those of patients with normal retinas by comprehensive gene and protein expression profiling 10, 11, 12. We have also detected increased levels of POSTN protein in the vitreous of patients with PDR 13 …”

Section: Introductionmentioning

confidence: 59%

“…Thus, therapies that block VEGF to inhibit pathological NV could result in unexpected complications of the normal retina and should be used cautiously. In contrast to VEGF, we have reported that POSTN was barely detectable in the normal retina 10, 13. We also reported that the correlation between the vitreous concentration of POSTN and VEGF was weak in patients with PDR 13 .…”

Section: Discussionmentioning

confidence: 77%

See 1 more Smart Citation

Therapeutic Effect of Novel Single-Stranded RNAi Agent Targeting Periostin in Eyes with Retinal Neovascularization

Nakama

Ishikawa

Kubo

et al. 2017

Molecular Therapy - Nucleic Acids

View full text Add to dashboard Cite

Retinal neovascularization (NV) due to retinal ischemia remains one of the principal causes of vision impairment in patients with ischemic retinal diseases. We recently reported that periostin (POSTN) may play a role in the development of preretinal fibrovascular membranes, but its role in retinal NV has not been determined. The purpose of this study was to examine the expression of POSTN in the ischemic retinas of a mouse model of oxygen-induced retinal NV. We also studied the function of POSTN on retinal NV using Postn KO mice and human retinal endothelial cells (HRECs) in culture. In addition, we used a novel RNAi agent, NK0144, which targets POSTN to determine its effect on the development of retinal NV. Our results showed that the expression of POSTN was increased in the vascular endothelial cells, pericytes, and M2 macrophages in ischemic retinas. POSTN promoted the ischemia-induced retinal NV by Akt phosphorylation through integrin αvβ3. NK0144 had a greater inhibitory effect than canonical double-stranded siRNA on preretinal pathological NV in vivo and in vitro. These findings suggest a causal relationship between POSTN and retinal NV, and indicate a potential therapeutic role of intravitreal injection of NK0144 for retinal neovascular diseases.

show abstract

Section: Introductionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 77%

Therapeutic Effect of Novel Single-Stranded RNAi Agent Targeting Periostin in Eyes with Retinal Neovascularization

Nakama

Ishikawa

Kubo

et al. 2017

Molecular Therapy - Nucleic Acids

View full text Add to dashboard Cite

show abstract

“…Previous studies of PDR have mainly focused on gene expression in FVMs or biomarkers in the vitreous (29,30). Although FVMs from PDR may be highly informative pathological tissues, they are largely unstudied.…”

Section: Discussionmentioning

confidence: 99%

Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis

Lam

Wong

et al. 2017

Diabetes

View full text Add to dashboard Cite

Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world’s working adult population and affects those with type 1 and type 2 diabetes. We identified Runt-related transcription factor 1 (RUNX1) as a gene upregulated in CD31+ vascular endothelial cells obtained from human PDR fibrovascular membranes (FVMs) via transcriptomic analysis. In vitro studies using human retinal microvascular endothelial cells (HRMECs) showed increased RUNX1 RNA and protein expression in response to high glucose, whereas RUNX1 inhibition reduced HRMEC migration, proliferation, and tube formation. Immunohistochemical staining for RUNX1 showed reactivity in vessels of patient-derived FVMs and angiogenic tufts in the retina of mice with oxygen-induced retinopathy, suggesting that RUNX1 upregulation is a hallmark of aberrant retinal angiogenesis. Inhibition of RUNX1 activity with the Ro5–3335 small molecule resulted in a significant reduction of neovascular tufts in oxygen-induced retinopathy, supporting the feasibility of targeting RUNX1 in aberrant retinal angiogenesis.

show abstract

“…70 In a transcriptomic analysis of fibrovascular membranes, angiogenesis appeared to be differentially expressed in PDR patients, along with ECM pathways. 71 Furthermore, altered levels of pigment epithelium-derived factor (PEDF) and clusterin (apolipoprotein J), which are both regulators of angiogenesis, have been identified frequently in proteomic studies. 70,[72][73][74][75][76][77][78] In addition, other members of the apolipoprotein family are regularly identified (Supplementary Table S2).…”

Section: Diabetic Retinopathy (Dr)mentioning

confidence: 99%

Omics Biomarkers in Ophthalmology

Jong

Lefeber

et al. 2017

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

''Omics'' refers to high-throughput analyses of genes, proteins, or metabolites in a biological system, and is increasingly used for ophthalmic research. These system-based approaches can unravel disease-related processes and are valuable for biomarker discovery. Furthermore, potential therapeutic targets can be identified based on omics results, and targeted follow-up experiments can be designed to gain molecular understanding of the disease and to test new therapies. Here, we review the application of omics techniques in eye diseases, focusing on age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal detachment (RD), myopia, glaucoma, Fuchs' corneal dystrophy (FCD), cataract, keratoconus, and dry eyes. We observe that genomic analyses were mainly successful in AMD research (almost half of the genomic heritability has been explained), whereas large parts of disease variability or risk remain unsolved in most of the other diseases. Other omics studies like transcriptomics, proteomics, and metabolomics provided additional candidate proteins and pathways for several eye diseases, although sample sizes in these studies were often very small and replication is lacking. In order to translate omics results into clinical biomarkers, larger sample sizes and validation across different cohorts would be essential. In conclusion, omicsbased studies are increasing in ophthalmology, and further application to the clinic might develop in the years to come. Integration of genomics with other type of omics data has the potential to improve the accuracy of predictive tests. Moreover, in the future, omics may lead to stratification of patients into subgroups based on molecular profiles, enabling the development of personalized treatments.

show abstract

Microarray Analysis of Gene Expression in Fibrovascular Membranes Excised From Patients With Proliferative Diabetic Retinopathy

Abstract: Our data indicate that extracellular matrix-related molecules such as POSTN, TNC, TGFβ, and angiogenic factors have important roles in promoting the development of FVMs associated with PDR.

Cited by 59 publications

References 46 publications

Therapeutic Effect of Novel Single-Stranded RNAi Agent Targeting Periostin in Eyes with Retinal Neovascularization

Therapeutic Effect of Novel Single-Stranded RNAi Agent Targeting Periostin in Eyes with Retinal Neovascularization

Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis

Omics Biomarkers in Ophthalmology

Contact Info

Product

Resources

About