Proteomic Insight into the Molecular Function of the Vitreous

Skeie, Jessica M.; Roybal, C. Nathaniel; Mahajan, Vinit B.

doi:10.1371/journal.pone.0127567

Cited by 80 publications

(101 citation statements)

References 52 publications

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“…Addressing the neurodegenerative aspect of NIV will require further molecular characterization of cell death biomarkers rather than cytokine biomarkers in NIV eyes. Our investigations of animal models suggest that retinal biomarkers may also be detected in liquid vitreous biopsies (32)(33)(34).…”

Section: Discussionmentioning

confidence: 80%

Therapeutic drug repositioning using personalized proteomics of liquid biopsies

Vélez¹,

Bassuk²,

Colgan³

et al. 2017

JCI Insight

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IntroductionAfter spending several billion dollars and a decade or more in development and clinical trial, only approximately 10% of new drugs show efficacy and reach the market for patient use. This apparent inefficiency, however, masks enormous opportunities to repurpose existing drugs to treat diseases for which they were not originally intended, especially diseases with limited therapeutic options (1, 2). Therapies for inflammatory diseases are an attractive choice for drug repositioning because of the complexity of the immune response, the hit-or-miss nature of treatment (which is often by trial and error), and the number of traditional drugs and new biologics for inflammatory diseases.Determining which drugs to reposition, however, is not trivial. Among a heterogeneous patient population that seems affected by the same autoimmune condition, one cannot be sure if the disease is in fact the same, or at what progressive stage a patient is presenting. Currently, most predictions of patients that would benefit from drug repositioning are drawn from retrospective computational methods, genomic analyses, BACKGROUND. In patients with limited response to conventional therapeutics, repositioning of already approved drugs can bring new, more effective options. Current drug repositioning methods, however, frequently rely on retrospective computational analyses and genetic testing -time consuming methods that delay application of repositioned drugs. Here, we show how proteomic analysis of liquid biopsies successfully guided treatment of neovascular inflammatory vitreoretinopathy (NIV), an inherited autoinflammatory disease with otherwise poor clinical outcomes.

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Section: Discussionmentioning

confidence: 80%

Therapeutic drug repositioning using personalized proteomics of liquid biopsies

Vélez¹,

Bassuk²,

Colgan³

et al. 2017

JCI Insight

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“…To identify proteins that regulate oxidative stress in the retina and vitreous, we interrogated human proteomics datasets [15] using gene ontology (GO) analysis [16]. There were 75 proteins in the human retina and vitreous categorized as oxidoreductases (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Three antioxidant proteins were unique to the vitreous: superoxide dismutase-3 (SOD3), eosinophil peroxidase (EPX), and arachidonate 5-lipoxygenase-activating protein (ALOX5AP; Fig. 1B) [15]. A network of these interacting proteins was generated (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface

Wert

Vélez

Cross

et al. 2018

Free Radical Biology and Medicine

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Oxidative stress is a pathogenic feature in vitreoretinal disease. However, the ability of the inner retina to manage metabolic waste and oxidative stress is unknown. Proteomic analysis of antioxidants in the human vitreous, the extracellular matrix opposing the inner retina, identified superoxide dismutase-3 (SOD3) that localized to a unique matrix structure in the vitreous base and cortex. To determine the role of SOD3, Sod3−/− mice underwent histological and clinical phenotyping. Although the eyes were structurally normal, at the vitreoretinal interface Sod3−/− mice demonstrated higher levels of 3-nitrotyrosine, a key marker of oxidative stress. Pattern electroretinography also showed physiological signaling abnormalities within the inner retina. Vitreous biopsies and epiretinal membranes collected from patients with diabetic vitreoretinopathy (DVR) and a mouse model of DVR showed significantly higher levels of nitrates and/or 3-nitrotyrosine oxidative stress biomarkers suggestive of SOD3 dysfunction. This study analyzes the molecular pathways that regulate oxidative stress in human vitreous substructures. The absence or dysregulation of the SOD3 antioxidant at the vitreous base and cortex results in increased oxidative stress and tissue damage to the inner retina, which may underlie DVR pathogenesis and other vitreoretinal diseases.

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“…Using the eye as a continuation of the CNS, potential biomarkers identified within the eye could be utilized to reflect what is happening within the brain, as fluid samples from the vitreous are easily obtained 43, 44, 45, 46. Additionally, advances in ocular imaging techniques could lead to noninvasive diagnosis of CNS injury.…”

Section: Discussionmentioning

confidence: 99%

Acute vitreoretinal trauma and inflammation after traumatic brain injury in mice

Evans

Newell

Mahajan

et al. 2018

Ann Clin Transl Neurol

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ObjectiveLimited attention has been given to ocular injuries associated with traumatic brain injury (TBI). The retina is an extension of the central nervous system and evaluation of ocular damage may offer a less‐invasive approach to gauge TBI severity and response to treatment. We aim to characterize acute changes in the mouse eye after exposure to two different models of TBI to assess the utility of eye damage as a surrogate to brain injury.MethodsA model of blast TBI (bTBI) using a shock tube was compared to a lateral fluid percussion injury model (LFPI) using fluid pressure applied directly to the brain. Whole eyes were collected from mice 3 days post LFPI and 24 days post bTBI and were evaluated histologically using a hematoxylin and eosin stain.Results bTBI mice showed evidence of vitreous detachment in the posterior chamber in addition to vitreous hemorrhage with inflammatory cells. Subretinal hemorrhage, photoreceptor degeneration, and decreased cellularity in the retinal ganglion cell layer was also seen in bTBI mice. In contrast, eyes of LFPI mice showed evidence of anterior uveitis and subcapsular cataracts.InterpretationWe demonstrated that variations in the type of TBI can result in drastically different phenotypic changes within the eye. As such, molecular and phenotypic changes in the eye following TBI may provide valuable information regarding the mechanism, severity, and ongoing pathophysiology of brain injury. Because vitreous samples are easily obtained, molecular changes within the eye could be utilized as biomarkers of TBI in human patients.

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Proteomic Insight into the Molecular Function of the Vitreous

Cited by 80 publications

References 52 publications

Therapeutic drug repositioning using personalized proteomics of liquid biopsies

Therapeutic drug repositioning using personalized proteomics of liquid biopsies

Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface

Acute vitreoretinal trauma and inflammation after traumatic brain injury in mice

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