Identification of Novel Choroidal Neovascularization-Related Genes Using Laplacian Heat Diffusion Algorithm.
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ABSTRACT:
SUBMITTER: Sheng M
PROVIDER: S-EPMC8440095 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cancer driver gene is a type of gene with abnormal alterations that initiate or promote tumorigenesis. Driver genes can be used to reveal the fundamental pathological mechanisms of tumorigenesis. These genes may have pathological changes at different omics levels. Thus, identifying cancer driver genes involving two or more omics levels is essential. In this study, a computational investigation was conducted on lung cancer driver genes. Four omics levels, namely, epigenomics, genomics, transcriptomics, and post-transcriptomics, were involved. From the driver genes at each level, the Laplacian heat diffusion algorithm was executed on a protein-protein interaction network for discovering latent driver genes at this level. A following screen procedure was performed to extract essential driver genes, which contained three tests: permutation, association, and function tests, which can exclude false-positive genes and screen essential ones. Finally, the intersection operation was performed to obtain novel driver genes involving two omic levels. The analyses on obtained genes indicated that they were associated with fundamental pathological mechanisms of lung cancer at two corresponding omics levels.
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Project description:BackgroundAge-related degeneration (AMD) and asthma are both diseases that are related to the activation of the complement system. The association between AMD and asthma has been debated in previous studies. The authors investigated the relationship between AMD and asthma systemically.Principal findingsThe epidemiological study showed that asthma was related to choroidal neovascularization (CNV) subtype (OR?=?1.721, P?=?0.023). However, the meta-analysis showed there was no association between AMD and asthma. In an animal model, we found more fluoresce in leakage of CNV lesions by FA analysis and more angiogenesis by histological analysis in rats with asthma. Western blot demonstrated an elevated level of C3?-chain, C3?'-chain and VEGF. After compstatin was intravitreally injected, CNV leakage decreased according to FA analysis, with the level of C3 and VEGF protein decreasing at the same time.SignificanceThis study first investigated the relationship between AMD and asthma systematically, and it was found that asthma could be a risk factor for the development of AMD. The study may provide a better understanding of the disease, which may advance the potential for screening asthma patients in clinical practice.
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Project description:PurposeTo use optical coherence tomography angiography (OCTA) to study longitudinal subclinical choroidal neovascularization (CNV) changes and their correlation with progression to exudation in age-related macular degeneration (AMD).MethodsThis study included a total of 34 patients with unilateral neovascular AMD who were evaluated prospectively using OCTA to detect subclinical CNV in their fellow eye. Eyes with baseline subclinical CNV were followed with serial OCTA for a minimum of one year (15.2±3.27 months) to monitor the development of exudation.ResultsOf the 34 fellow eyes studied, five were found to have baseline subclinical CNV. One of the five cases of baseline subclinical CNV converted to exudative AMD during the follow up period. The average surface area of baseline subclinical CNV on OCTA was 0.131±0.096 mm2 which progressed to 0.136±0.104 mm2 at the final follow up (P = 0.539). Geographic atrophy grew at a rate of 0.82±1.20mm2/year in four eyes without subclinical CNV and 0.02mm2/year in one eye with subclinical CNV.Conclusion and importanceThe rate of conversion to exudative AMD in eyes with subclinical CNV of 20% in our study is similar to previous reports and suggests the importance of vigilance in these eyes. The lower growth rate of geographic atrophy may suggest a protective effect of subclinical CNV that deserves further study.
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Project description:Age-related macular degeneration (AMD) is a leading cause of severe vision loss in older individuals in developed countries. Despite advances in our understanding of AMD, its pathophysiology remains poorly understood. Matrix metalloproteinases (MMPs) have been proposed to play a role in AMD development. In this study, we aimed to characterize MMP-13 in AMD. We used retinal pigment epithelial cells, a murine model of laser-induced choroidal neovascularization, and plasma samples from patients with neovascular AMD to conduct our study. Our results show that MMP13 expression significantly increased under oxidative stress conditions in cultured retinal pigment epithelial cells. In the murine model, MMP13 was overexpressed in both retinal pigment epithelial cells and endothelial cells during choroidal neovascularization. Additionally, the total MMP13 levels in the plasma of patients with neovascular AMD were significantly lower than those in the control group. This suggests a reduced diffusion from the tissues or release from circulating cells in the bloodstream, given that the number and function of monocytes have been reported to be deficient in patients with AMD. Although more studies are needed to elucidate the role of MMP13 in AMD, it could be a promising therapeutic target for treating AMD.
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Project description:Abnormal migration and proliferation of endothelial cells (EC) drive neovascular retinopathies. While anti-VEGF treatment slows progression, pathology is often supported by decrease in intraocular pigment epithelium-derived factor (PEDF), an endogenous inhibitor of angiogenesis. A surface helical 34-mer peptide of PEDF, comprising this activity, is efficacious in animal models of neovascular retina disease but remains impractically large for therapeutic use. We sought smaller fragments within this sequence that mitigate choroidal neovascularization (CNV). Expecting rapid intravitreal (IVT) clearance, we also developed a method to reversibly attach peptides to nano-carriers for extended delivery. Synthetic fragments of 34-mer yielded smaller anti-angiogenic peptides, and N-terminal capping with dicarboxylic acids did not diminish activity. Charge restoration via substitution of an internal aspartate by asparagine improved potency, achieving low nM apoptotic response in VEGF-activated EC. Two optimized peptides (PEDF 335, 8-mer and PEDF 336, 9-mer) were tested in a mouse model of laser-induced CNV. IVT injection of either peptide, 2-5 days before laser treatment, gave significant CNV decrease at day +14 post laser treatment. The 8-mer also decreased CNV, when administered as eye drops. Also examined was a nanoparticle-conjugate (NPC) prodrug of the 9-mer, having positive zeta potential, expected to display longer intraocular residence. This NPC showed extended efficacy, even when injected 14 days before laser treatment. Neither inflammatory cells nor other histopathologic abnormalities were seen in rabbit eyes harvested 14 days following IVT injection of PEDF 336 (>200 ?g). No rabbit or mouse eye irritation was observed over 12-17 days of PEDF 335 eye drops (10 mM). Viability was unaffected in 3 retinal and 2 choroidal cell types by PEDF 335 up to 100 ?M, PEDF 336 (100 ?M) gave slight growth inhibition only in choroidal EC. A small anti-angiogenic PEDF epitope (G-Y-D-L-Y-R-V) was identified, variants (adipic-Sar-Y-N-L-Y-R-V) mitigate CNV, with clinical potential in treating neovascular retinopathy. Their shared active motif, Y - - - R, is found in laminin (Ln) peptide YIGSR, which binds Ln receptor 67LR, a known high-affinity ligand of PEDF 34-mer.
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Project description:Perturbations in WNT signaling are associated with congenital eye disorders, including familial exudative vitreoretinopathy and Norrie disease. More recently, activation of the WNT pathway has also been shown to be associated with age-related macular degeneration (AMD). In this study, we identified that in choroidal neovascular membranes from AMD patients, ?-catenin is activated specifically in the vascular endothelium, suggesting that WNT promotes pathologic angiogenesis by directly affecting vascular endothelial cells. WNT7B has been shown to be important during eye development for regression of the fetal hyaloid vasculature. However, it has not yet been established whether WNT7A and/or WNT7B are involved in neovascular AMD pathogenesis. Here, we show that WNT7A and WNT7B increase the proliferation of human dermal microvascular endothelial cells in a dose-dependent manner. Both WNT7A and WNT7B also stimulated vascular sprouting from mouse choroidal explants in vitro. To evaluate in vivo relevance, we generated mice systemically deficient in Wnt7a and/or Wnt7b. Genetic deletion of both Wnt7a and Wnt7b decreased the severity of laser injury-induced choroidal neovascularization (CNV), while individual deletion of either Wnt7a or Wnt7b did not have a significant effect on CNV, suggesting that WNT7A and WNT7B have redundant pro-angiogenic roles in vivo. Cumulatively, these findings identify specific WNT isoforms that may play a pathologic role in CNV as observed in patients with neovascular AMD. Although the source of increased WNT7A and/or WNT7B in CNV requires further investigation, WNT signaling may be a potential target for therapeutic intervention if these results are demonstrated to be relevant in human disease.
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Project description:PURPOSE:Doxycycline, a broad-spectrum antibiotic, has certain antiangiogenic properties and can inhibit matrix metalloproteinases (MMPs/gelatinases). The authors investigated the effects of doxycycline on choroidal neovascularization (CNV) and regulation of MMP-2 and -9 and pigment epithelium-derived factor (PEDF). METHODS:Doxycycline was orally administered to rats at 500, 50, 5, and 0.5 mg/kg/d; nontreated animals were used as controls. Experimental CNV was induced with laser 7 days after doxycycline treatment started. At 7 days after induction, animals were euthanatized, and eyes were collected. RPE/choroid flatmounts were labeled with isolectin IB4 to determine CNV lesion volumes using confocal microscopy and high-performance 3D imaging software. MMP-2, MMP-9, and PEDF protein levels were determined by ELISA. MMP catalytic activity was determined in solution using fluorogenic gelatin and peptide substrates, by gelatin zymography in SDS-PAGE, and by in situ fluorogenic substrate zymography in RPE/choroid sections. RESULTS:CNV complex lesion volumes decreased with doxycycline in a dose-response relationship. A dosage of 500 mg/kg/d caused a 70% inhibition of CNV complex volume compared with control animals. Doxycycline elevated PEDF levels in plasma and did not affect the active and pro-enzymes MMP-2 and MMP-9 levels. However, the in vitro enzymatic activities of purified MMP-2 and MMP-9 declined significantly with doxycycline. MMP-2, MMP-9, and gelatinolytic activities in situ increased early in CNV lesion development. Doxycycline treatments and exogenous additions inhibited gelatinolytic activities in CNV lesions. CONCLUSIONS:Doxycycline effectively hampered the progression of experimental CNV. The results suggest that orally administrated doxycycline can reach the choroid to attenuate proteolytic enzymes that remodel Bruch's membrane and promote the antiangiogenic PEDF to inhibit neovascularization.
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Project description:Many conditions affecting the heart, brain, and even the eyes have their origins in blood vessel pathology, underscoring the role of vascular regulation. In age-related macular degeneration (AMD), there is excessive growth of abnormal blood vessels in the eye (choroidal neovascularization), eventually leading to vision loss due to detachment of retinal pigmented epithelium. As the advanced stage of this disease involves loss of retinal pigmented epithelium, much less attention has been given to early vascular events such as endothelial dysfunction. Although current gold standard therapy using inhibitors of vascular endothelial growth factor (VEGF) have achieved initial successes, some drawbacks include the lack of long-term restoration of visual acuity, as well as a subset of the patients being refractory to existing treatment, alluding us and others to hypothesize upon VEGF-independent mechanisms. Against this backdrop, we present here a nonexhaustive review on the vascular underpinnings of AMD, implications with genetic and systemic factors, experimental models for studying choroidal neovascularization, and interestingly, on both endothelial-centric pathways and noncell autonomous mechanisms. We hope to shed light on future research directions in improving vascular function in ocular disorders.
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