Protein kinase C inhibition and diabetic retinopathy: a shot in the dark at translational research.
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ABSTRACT:
SUBMITTER: Donnelly R
PROVIDER: S-EPMC1771919 | biostudies-literature | 2004 Jan
REPOSITORIES: biostudies-literature
Publications
Protein kinase C inhibition and diabetic retinopathy: a shot in the dark at translational research.
Donnelly R R Idris I I Forrester J V JV
The British journal of ophthalmology 20040101 1
TRANSLATIONAL RESEARCH IN PRACTICE: a PKC-beta inhibitor for diabetic retinopathy ...[more]
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Project description:PurposePrioritizing comparative effectiveness research may contribute to obtaining answers that clinicians perceive they need and may minimize research that could be considered wasteful. Our objective was to identify evidence gaps and set priorities for new systematic reviews and randomized controlled trials for managing diabetic retinopathy (DR), including diabetic macular edema (DME).DesignCross-sectional study.ParticipantsDiabetic Retinopathy Clinical Research Network (DRCR.net) investigators.MethodsWe provided recommendations from the American Academy of Ophthalmology's 2012 Preferred Practice Patterns for Diabetic Retinopathy as 91 answerable clinical research questions about intervention effectiveness to 410 DRCR.net investigators to rate each question's importance from 0 (not important) to 10 (very important) using a 2-round Delphi survey and to suggest additional questions. We considered questions as high priority if at least 75% of respondents to both rounds assigned an importance rating of 5 or more in round 2. We also extracted outcome measures relevant to DR and asked respondents to identify those that must be measured in all studies. We mapped Cochrane reviews published up to March 2016 to high-priority clinical research questions.Main outcome measureRanking of importance of each clinical question.ResultsThirty-two individuals completed rounds 1 and 2 and suggested 15 questions. Among the final list of 106 clinical research questions, 22 questions met our definition of high priority: 9 of 22 concerned the effectiveness of anti-VEGF therapy, and 13 of 22 focused on how often patients should be followed up (re-examination) and treatment effectiveness in patients with specific characteristics (e.g., DME). Outcomes that 75% or more of respondents marked as "must be measured in all studies" included visual acuity and visual loss, death of participants, and intraocular pressure. Only 1 prioritized question was associated with conclusive evidence from a Cochrane systematic review.ConclusionsA limited response rate among DRCR.net members identified 22 comparative effectiveness research questions as high priority for the management of DR, including DME, but few were associated with Cochrane reviews. These results support the need of systematic reviews and randomized controlled trials to address evidence gaps.
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Project description:ObjectiveDiabetic retinopathy (DR) is a common complication of diabetes, and recent findings have shown that long noncoding RNAs (lncRNAs) may be involved in its pathogenesis. Through bioinformatics analysis, we found that lncRNA ATP2B2-IT2 may be involved in this process. This study primarily investigated the expression of the lncRNA ATP2B2-IT2 in human retinal microvascular endothelial cells (HRMECs) under high-glucose conditions and its effects on HRMEC proliferation, migration, and neovascularization.MethodsWe used RT‒PCR to assess the expression levels of lncRNA ATP2B2-IT2 and vascular endothelial growth factor (VEGF) in HRMECs under normal glucose (5.5 mmol/L) and high glucose (30 mmol/L) conditions. HRMECs were subsequently divided into four groups: the normal glucose (NG), high glucose (HG), high glucose with lncRNA ATP2B2-IT2 silencing (HG + si-lncRNA ATP2B2-IT2), and high glucose with silencing control (HG + si-NC) groups. The expression levels of the lncRNA ATP2B2-IT2 and VEGF in each group were determined using RT‒PCR. Thereafter, cell proliferation, migration, and neovascularization were assessed using CCK-8, Transwell, and tube formation assays, respectively.ResultsRT‒PCR revealed that the expression levels of the lncRNA ATP2B2-IT2 and VEGF were greater in the HG group than in the NG group (P < 0.05). After silencing of the lncRNA ATP2B2-IT2, the expression of VEGF decreased significantly (P < 0.05). Subsequent CCK-8, Transwell, and tube formation assays demonstrated that compared to those in the NG group, the HRMECs in the HG group exhibited significantly increased proliferation, migration, and neovascularization (P < 0.05). However, after silencing of the lncRNA ATP2B2-IT2, the proliferation, migration, and neovascularization of HRMECs were significantly decreased in the HG + si-lncRNA ATP2B2-IT2 group compared to those in the HG group (P < 0.05).ConclusionLncRNA ATP2B2-IT2 may promote the proliferation, migration and neovascularization of HRMECs under high-glucose conditions.
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Project description:In addition to laser photocoagulation, therapeutic interventions for diabetic retinopathy (DR) have heretofore consisted of anti-VEGF drugs, which, besides drawbacks inherent to the treatments themselves, are limited in scope and may not fully address the condition's complex pathophysiology. This is because DR is a multifactorial condition, meaning a gene therapy focused on a target with broader effects, such as the mechanistic target of rapamycin (mTOR), may prove to be the solution in overcoming these concerns. Having previously demonstrated the potential of a mTOR-inhibiting shRNA packaged in a recombinant adeno-associated virus to address a variety of angiogenic retinal diseases, here we explore the effects of rAAV2-shmTOR-SD in a streptozotocin-induced diabetic mouse model. Delivered via intravitreal injection, the therapeutic efficacy of the virus vector upon early DR processes was examined. rAAV2-shmTOR-SD effectively transduced mouse retinas and therein downregulated mTOR expression, which was elevated in sham-treated and control shRNA-injected (rAAV2-shCon-SD) control groups. mTOR inhibition additionally led to marked reductions in pericyte loss, acellular capillary formation, vascular permeability, and retinal cell layer thinning, processes that contribute to DR progression. Immunohistochemistry showed that rAAV2-shmTOR-SD decreased ganglion cell loss and pathogenic Müller cell activation and proliferation, while also having anti-apoptotic activity, with these effects suggesting the therapeutic virus vector may be neuroprotective. Taken together, these results build upon our previous work to demonstrate the broad ability of rAAV2-shmTOR-SD to address aspects of DR pathophysiology further evidencing its potential as a human gene therapeutic strategy for DR.
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