Colm O'Brien

• Mater Misericordiae University Hospital

Lamina cribrosa (LC) cells play an integral role in extracellular matrix remodeling and fibrosis in human glaucoma. LC cells bear similarities to myofibroblasts that adopt an apoptotic-resistant, proliferative phenotype, a process linked to dysregulation of tumor suppressor-gene p53 pathways, including ubiquitin-proteasomal degradation via murine-d...

Purpose: Glaucoma, one of the leading causes of irreversible blindness, is a common progressive optic neuropathy characterised by visual field defects and structural changes to the optic nerve head (ONH). There is extracellular matrix (ECM) accumulation and fibrosis of the lamina cribrosa (LC) in the ONH, and consequently increased tissue stiffness...

Glaucoma, a leading cause of blindness, is a multifactorial condition that leads to progressive loss of retinal ganglion cells (RGCs) and vision. Therapeutic interventions based on reducing ocular hypertension are not always successful. Emerging features of glaucoma include mitochondrial dysfunction and oxidative stress. In the current study, NDI1-...

Précis Patients with glaucoma demonstrated deficiencies in their ability to process multi-sensory information when compared to controls, with those deficiencies being related to glaucoma severity. Impaired multi-sensory integration may affect the quality of life in individuals with glaucoma, and may contribute to the increased prevalence of falls a...

Optic nerve head (ONH) cupping is a clinical feature of glaucoma associated with extracellular matrix (ECM) remodelling and lamina cribrosa (LC) fibrosis. Peripapillary atrophy (PPA) occurs commonly in glaucoma, and is characterised by the loss of retinal pigment epithelium (RPE) adjacent to the ONH. Under pro-fibrotic conditions, epithelial cells...

Organ fibrosis represents a dysregulated, maladaptive wound repair response that results in progressive disruption of normal tissue architecture leading to detrimental deterioration in physiological function, and significant morbidity/mortality. Fibrosis is thought to contribute to nearly 50% of all deaths in the Western world with current treatmen...

Glaucoma is one of the most common causes of treatable visual impairment in the developed world, affecting approximately 64 million people worldwide, some of whom will be bilaterally blind from irreversible optic nerve damage. The optic nerve head is a key site of damage in glaucoma where there is fibrosis of the connective tissue in the lamina cri...

Primary open angle glaucoma (POAG), a chronic optic neuropathy, remains the leading cause of irreversible blindness worldwide. It is driven in part by the pro-fibrotic cytokine transforming growth factor beta (TGF-β) and leads to extracellular matrix remodelling at the lamina cribrosa of the optic nerve head. Despite an array of medical and surgica...

It is known that as people age their tissues become less compliant and the ocular structures are no different. Corneal Hysteresis (CH) is a surrogate marker for ocular compliance. Low hysteresis values are associated with optic nerve damage and visual field loss, the structural and functional components of glaucomatous optic neuropathy. Presently,...

Glaucoma is the leading cause of irreversible blindness worldwide, and the burden of the disease continues to grow as the global population ages. Currently, the only treatment option is to lower intraocular pressure. A better understanding of glaucoma pathogenesis will help us to develop novel therapeutic options. Oxidative stress has been implicat...

Glaucoma is a progressive, age-related optic neuropathy, whereby the prevalence increases sharply over the age of 60 and is associated with increased systemic tissue stiffness. On a molecular basis, this is associated with increased deposition of collagen and loss of elastin structure, resulting in aberrant biomechanical compliance and reduced tiss...

Background Glaucoma is the leading cause of irreversible blindness globally. During the COVID-19 pandemic, an enforced reduction in capacity resulted in the deferral of routine outpatient appointments for glaucoma patients.AimThis study analyses patient outcomes following the establishment of a drive-through intra-ocular pressure (IOP) clinic durin...

Purpose: Extracellular matrix stiffening is characteristic of both aging and glaucoma, and acts as a promoter and perpetuator of pathological fibrotic remodeling. Here, we investigate the role of a mechanosensitive transcriptional coactivator, Yes-associated protein (YAP), a downstream effector of multiple signaling pathways, in lamina cribrosa (L...

Purpose Primary open-angle glaucoma (POAG) is an age-related fibrotic condition and a leading cause of blindness worldwide. POAG-related damage is initiated within the lamina cribrosa (LC) region of the optic nerve head, driven by the pathological activation of resident LC cells. LC cells bear striking similarities to proliferative, apoptotic-resis...

Previous studies have shown that glaucomatous Schlemm’s canal endothelial cells (gSCECs) are stiffer and associated with reduced porosity and increased extracellular matrix (ECM) material compared to SCECs from healthy individuals. We hypothesised that Schlemm’s canal (SC) cell stiffening was a function of fibrotic changes occurring at the inner wa...

Glaucoma is the leading cause of irreversible blindness globally. With an aging population, disease incidence will rise with an enormous societal and economic burden. The treatment strategy revolves around targeting intraocular pressure, the principle modifiable risk factor, to slow progression of disease. However, there is a clear unmet clinical n...

Purpose To evaluate the macular pigment response to carotenoid supplementation in glaucomatous eyes. Design A double masked, randomized and placebo-controlled clinical trial, the European Nutrition In Glaucoma Management (ENIGMA) study (ClinicalTrials.gov Identifier: NCT04460365). Participants Sixty-two participants (38 male, 24 female) with a di...

Glaucoma is a common progressive optic neuropathy that results in visual field defects and can lead to irreversible blindness. The pathophysiology of glaucoma involves dysregulated extracellular matrix remodelling in both the trabecular meshwork in the anterior chamber and in the lamina cribrosa of the optic nerve head. Fibrosis in these regions le...

Objective We aimed to carry out ocular examination and genetic studies in a family in which some members are affected with osteogenesis imperfecta (OI) and primary open-angle glaucoma (POAG). We compared the corneal properties of affected and unaffected members (ie, cases and controls). Methods Eight family members from two generations, both affec...

The lamina cribrosa (LC) is a key site of fibrotic damage in glaucomatous optic neuropathy and the precise mechanisms of LC change remain unclear. Elevated Ca2+ is a major driver of fibrosis, and therefore intracellular Ca2+ signaling pathways are relevant glaucoma-related mechanisms that need to be studied. Protein kinase C (PKC), mitogen-activate...

Pseudoexfoliation syndrome (PXF) is the most common cause of secondary open angle glaucoma worldwide. Single nucleotide polymorphisms (SNPs) in the gene Lysyl oxidase like 1 (LOXL1) are strongly associated with the development of pseudoexfoliation glaucoma (PXFG). However, these SNPs are also present in 50-80% of the general population, suggestive...

Purpose: The lamina cribrosa (LC) is a key site of damage in glaucomatous optic neuropathy. We previously found that glaucoma LC cells have an increased profibrotic gene expression, with mitochondrial dysfunction in the form of decreased mitochondrial membrane potential. Altered cell bioenergetics have recently been reported in organ fibrosis and...

Systemic or localised application of glucocorticoids (GC) can lead to iatrogenic ocular hypertension, which is a leading cause of secondary open angle glaucoma and visual impairment. Previous work has shown that dexamethasone increases zonula occludens-1 (ZO-1) protein expression in trabecular meshwork (TM) cells, and that an antisense oligonucleot...

The primary biomechanical driver of pathological glaucomatous cupping remains unknown. Finite element modelling indicates that stress and strain play key roles. Primarily a review article we utilise known biomechanical data and currently unpublished results from our lab to propose a 3 stage, tissue stiffness-based model to explain glaucomatous cupp...

Biomechanical properties of the cornea have recently emerged as clinically useful in risk assessment of diagnosing glaucoma and predicting disease progression. Corneal hysteresis (CH) is a dynamic tool, which measures viscoelasticity of the cornea. It represents the overall deformability of the cornea, and reduces significantly with age. Low CH has...

The lamina cribrosa (LC) in glaucoma is with augmented production of extracellular matrix proteins (ECM) and connective tissue fibrosis. Fundamental pathological mechanisms for this fibrosis comprise fibrotic growth factors and oxidative stress. Transient receptor potential canonical channels (TRPC) channels play a key role in ECM fibrosis. Here, w...

Precis: High risk alleles of risk-associated SNPs within the LOXL1 gene are associated with pseudoexfoliation in patients recruited from an Irish population. Purpose: Single nucleotide polymorphisms (SNPs) within the lysyl oxidase-like (LOXL) 1 gene have been identified as a major risk factor for pseudoexfoliation syndrome (PXF) and PXF glaucoma...

Purpose Lysyl oxidase like 1 (LOXL1) catalyzes collagen and elastin crosslinking. Single nucleotide polymorphisms (SNPs) within LOXL1 are associated with pseudoexfoliation (PXF) syndrome and PXF glaucoma (PXFG). These SNPs are present in 50%–80% of the general population, suggesting environmental factors also play a role in disease development. Our...

Purpose Glaucoma is an optic neuropathy and a leading cause of irreversible blindness worldwide. Although there are many factors that may contribute to disease predisposition, severity and progression, pseudoexfoliation (PXF) syndrome represents a significant cause for developing open angle glaucoma. Single nucleotide polymorphisms (SNPs) within th...

Background Myopia is becoming increasingly prevalent throughout the world. It is an overlooked but leading cause of blindness, particularly among the working aged population. Myopia is often considered benign because it is easily corrected with glasses, contact lenses or refractive surgery. Traditionally myopia has been classified into physiologica...

Cell differentiation is directed by extracellular cues and intrinsic epigenetic modifications, which control chromatin organization and transcriptional activation. Central to this process is PRC2, which modulates the di‐ and trimethylation of lysine 27 on histone 3; however, little is known concerning the direction of PRC2 to specific loci. Here, w...

Current treatment strategies for glaucoma are limited to halting disease progression and do not restore lost visual function. Intraocular pressure is the main risk factor for glaucoma, and intraocular pressure–lowering treatment remains the mainstay of glaucoma treatment, but even successful intraocular pressure reduction does not stop the progress...

In this review, we present an update on biomarkers (both clinical and laboratory) on the basis of recent peer-reviewed publications relating to pseudoexfoliation syndrome and pseudoexfoliation glaucoma.

Background: Patients at glaucoma risk are commonly identified by optometrists and subsequently referred to glaucoma specialists. Optometrists mainly use non-contact tonometry (NCT) for intraocular pressure (IOP) measurement. Aims: To investigate the role of differences in IOP measurement between NCT and Goldmann applanation tonometry (GAT) and t...

Purpose: Glaucoma referral refinement (GRR) has proven a successful demand management strategy for glaucoma suspect cases in the United Kingdom (UK). A GRR clinic was established in Dublin, Ireland to investigate the clinical viability of this pathway outside the UK's National Health Service (NHS) structures, and away from the influence of Nationa...

Purpose: Optic nerve cupping in glaucoma is characterized by remodeling of the extracellular matrix (ECM) and fibrosis in the lamina cribrosa (LC). We have previously shown that glaucoma LC cells express raised levels of ECM genes and have elevated intracellular calcium ([Ca2+]i). Raised [Ca2+]i is known to promote proliferation, activation, and c...

Purpose: Alteration in the extracellular matrix (ECM) of the optic nerve head (ONH) causes lamina cribrosa (LC) fibrosis and affects the mechanical integrity of the ONH. Increased ECM tissue stiffness drives myofibroblast activation leading to tissue fibrosis throughout the body. Here using primary human LC cells, we investigate the effect of subs...

Aim To evaluate the relationship between macular pigment optical density (MPOD) and glare disability in open-angle glaucoma. Methods A cross-sectional analysis of baseline data (88 subjects; median age, 67 (range 36–84) years) collected during the Macular Pigment and Glaucoma Trial (ISRCTN registry number: 56985060). MPOD at 0.25°, 0.5° and 1° of...

Background: This research was designed to provide an in-depth exploration of the perceptions of optometrists relating to the challenges of glaucoma case finding in the Irish health-care system. Methods: A survey was developed, piloted and distributed for anonymous completion by optometrists registered to practise in Ireland. The survey included...

Glaucoma is a progressive and chronic neurodegenerative disorder characterised by damage to the inner layers of the retina and deformation of the optic nerve head. The degeneration of retinal ganglion cells (RGCs) and their axons results in an irreversible loss of vision and is correlated with increasing age. Extracellular matrix (ECM) changes rela...

Mitochondrial dysfunction commonly presents with ocular findings as a part of a systemic disorder. These ophthalmic manifestations can be the first sign of a mitochondrial abnormality, which highlights the key role of a comprehensive ophthalmic assessment. On the other hand, a number of visually disabling genetic and acquired eye diseases with no c...

Intraocular pressure (IOP) is maintained as a result of the balance between production of aqueous humour (AH) by the ciliary processes and hydrodynamic resistance to its outflow through the conventional outflow pathway comprising the trabecular meshwork (TM) and Schlemm’s canal (SC). Elevated IOP, which can be caused by increased resistance to AH o...

The juxtacanalicular connective tissue of the trabecular meshwork together with inner wall endothelium of Schlemm’s canal (SC) provide the bulk of resistance to aqueous outflow from the anterior chamber. Endothelial cells lining SC elaborate tight junctions (TJs), down-regulation of which may widen paracellular spaces between cells, allowing greate...

Background To compare corneal hysteresis (CH) measurements between patients with glaucoma, ocular hypertension (OHT) and glaucoma-like optic discs (GLD)- defined as a cup to disc ratio greater than or equal to 0.6 with normal intraocular pressure (IOP) and visual fields. The secondary aim was to investigate whether corneal resistance factor (CRF) a...

Primary open-angle glaucoma is a multifactorial blinding disease often impacting the two pressure-sensitive regions of the eye: the conventional outflow pathway and the optic nerve head (ONH). The connective tissues that span these two openings in the globe are the trabecular meshwork of the conventional outflow pathway and the lamina cribrosa of t...

Background: Glaucoma is an optic neuropathy that affects 60 million people worldwide. There is an underlying fibrosis associated with the lamina cribrosa (LC) in glaucoma. DNA methylation is well established in regulating fibrosis and may be a therapeutic target for glaucoma. The purpose of this study was to compare global DNA methylation levels i...

Purpose: Fibrosis and a hypoxic environment are associated with the trabecular meshwork (TM) region in the blinding disease glaucoma. Hypoxia has been shown to alter DNA methylation, an epigenetic mechanism involved in regulating gene expression such as the pro-fibrotic transforming growth factor (TGF) β1 and the anti-fibrotic Ras protein activato...

Glaucoma is a chronic progressive optic neuropathy. There are extracellular matrix (ECM) changes associated with optic disc cupping in the optic nerve head (ONH) and subsequent visual field defects. The primary risk factor for onset and progression of glaucoma is raised intraocular pressure (IOP). Elevated IOP causes deformation at the ONH specific...

Pseudoexfoliation syndrome (PXS) and pigment dispersion syndrome (PDS) are two of the commonest disorders to produce secondary open-angle glaucoma through trabecular meshwork blockage. Each is a defined clinical entity, and while genetics likely play a significant role in the pathogenesis of both, the specific genes involved appear to be distinct....

Purpose To determine the prevalence of glaucoma among patients referred to a glaucoma service with suspicious disc photographs from the diabetic retinopathy (DR) screening program. Methods A clinical audit of all patients attending a single-center DR screening program in the Mater Misericordiae University Hospital, Dublin, between July 2010 and Oc...

. Altered ocular perfusion and vascular dysregulation have been reported in glaucoma. The aim of this paper was to evaluate the vascular response to a hypercapnic stimulus. Methods . Twenty normal tension glaucoma (NTG) patients and eighteen age- and gender-matched controls had pulsatile ocular blood flow (POBF) measurements, systemic cardiovascula...

To evaluate the relationship between macular pigment optical density (MPOD) and structural parameters of the macula and optic nerve head in glaucomatous eyes. A cross-sectional analysis of the baseline data collected during the Macular Pigment and Glaucoma Trial (ISRCTN registry number: 56985060). Eighty-eight subjects (48 male, 40 female) with a d...

We performed a literature synthesis to identify the full spectrum of compounds implicated in drug-induced, bilateral secondary angle-closure glaucoma (2° ACG). Systematic PubMed literature review identified relevant bilateral 2° ACG case reports. We evaluated these reports with both the Naranjo adverse drug reaction probability scale to assess the...

To review the current literature regarding the role of matricellular proteins in glaucoma, specifically in the lamina cribrosa (LC) region of the optic nerve head (ONH) and the trabecular meshwork (TM). A literature search was performed for published articles describing the expression and function of matricellular proteins such as thrombospondin (T...

This study examines the effect of the L-type calcium channel blocker verapamil on mechanical strain-induced extracellular matrix genes in optic nerve head lamina cribrosa (LC) cells. Changes in LC cell intracellular calcium [Ca(2+)]i following hypotonic cell membrane stretch were measured with the fluorescent probe fura-2/AM. Fluorescence intensity...

Disease associated alterations in the phenotype of lamina cribrosa (LC) cells are implicated in changes occurring at the optic nerve head (ONH) in glaucoma. Lipofuscin, the formation of which is driven by reactive oxygen species (ROS), is an intralysosomal, non-degradable, auto-fluorescent macromolecule which accumulates with age and can affect aut...

Glaucoma is a neurodegenerative disorder characterised by damage to inner layers of the retina and the optic nerve (ON). The slow degeneration of retinal ganglion cells (RGCs) and their axons results in a progressive loss of vision. To date, a wide variety of animal models have been used to study glaucoma disease mechanisms and these include monkey...

Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and hence have a profound effect in lowering serum cholesterol. Their predominant clinical use to date is in primary and secondary prevention of cardiovascular disease. However recently interest has developed regarding the so-called “pleiotropic” effects of statin...

It is currently estimated that 60 to 70 million people worldwide are affected by open-angle glaucoma and the majority of patients who present to clinic have raised intraocular pressure, visual field loss, and cupping of the optic nerve. Although exfoliation glaucoma (XFG) correlates with age, it is the most common cause of secondary open-angle glau...

Purpose: The aim of this study was to determine whether mutations in mitochondrial DNA play a role in high-pressure primary open-angle glaucoma (OMIM 137760) by analyzing new data from massively parallel sequencing of mitochondrial DNA. Methods: Glaucoma patients with high-tension primary open-angle glaucoma and ethnically matched and age-matche...

The risk factors associated with optic disc cupping in glaucoma include intraocular pressure and ocular perfusion pressure. The mechanisms of optic disc cupping result in significant extra-cellular matrix alterations for the lamina cribrosa. A number of cell types play a key role in this ECM re-modelling including lamina cribrosa cells and astrocyt...

Glaucoma is an optic neuropathy affecting approximately 60 million people worldwide and is the second most common cause of irreversible blindness. Elevated intraocular pressure (IOP) is the main risk factor for developing glaucoma and is caused by impaired aqueous humor drainage through the trabecular meshwork (TM) and Schlemm's canal (SC). In prim...

Hyperglycaemia and hypoxia play essential pathophysiological roles in diabetes. We determined whether hyperglycaemia influences endothelial cell growth under hypoxic conditions in vitro. Using a Ruskinn Invivo2 400 Hypoxia Workstation, bovine aortic endothelial cells (BAEC) were exposed to high glucose concentrations (25 mM glucose) under normoxic...

Glaucoma is an optic neuropathy that affects 60 million people worldwide. The main risk factor for glaucoma is increased intraocular pressure (IOP), this is currently the only target for treatment of glaucoma. However, some patients show disease progression despite well-controlled IOP. Another possible therapeutic target is the extracellular matrix...

Purpose: We have previously demonstrated elevated levels of connective tissue growth factor (CTGF/CCN2) in the aqueous humor (AqH) of pseudoexfoliation glaucoma (PXFG) patients when compared with cataract controls. Furthermore, there is a significant trabecular meshwork (TM) and lamina cribrosa (LC) fibrotic phenotype associated with glaucoma, pos...

The connective tissue plates of the lamina cribrosa (LC) region are continuously exposed to a mechanically dynamic environment. To study how the LC cells respond to these mechanical forces, we measured the mechano-sensitive calcium dependent maxi-K(+) ion channel current in the cell membrane of LC cells of glaucoma and normal subjects. Primary cult...

Background/aims: Macular pigment (MP) plays an important role in visual function and in the protection of the retina from oxidative damage. It is not known whether glaucoma, a progressive neurodegenerative disease of the optic nerve, is associated with alterations in MP. This study was designed to investigate the relationship, if any, between the...

Loss of vision in glaucoma is due to apoptotic retinal ganglion cell loss. While p53 modulates apoptosis, gene association studies between p53 variants and glaucoma have been inconsistent. In this study we evaluate the association between a p53 variant functionally known to influence apoptosis (codon 72 Pro/Arg) and the subset of primary open angle...

Vascular hypoperfusion, extracellular matrix remodeling and axon loss are pathological characteristics of the glaucomatous optic nerve head. We report a novel study demonstrating transcriptional responses in optic nerve lamina cribrosa (LC) cells exposed to in vitro hypoxic stress. Primary cultures of human glial fibrillary acid protein (GFAP) nega...

Aberrant retinal blood flow is a hallmark of retinopathies and may be a causative factor in their pathophysiology. In this study, the effects of pulsatile flow on hedgehog and Notch control of retinal endothelial cell and pericyte apoptosis were examined. The levels of hedgehog and Notch signaling components in bovine retinal endothelial cells (BRE...

The loss of vision is associated with the impairment of functional ability, including a reduced ability to move around and to utilise all forms of transport. Walking in unfamiliar environments is challenging and driving becomes a legal prohibition. This article explores mobility and access to transport issues of urban and rural dwelling people with...

Purpose: Pseudoexfoliation syndrome (PXF) is a generalised disorder of the extracellular matrix (ECM) involving the trabecular meshwork (TM), associated with raised intraocular pressure, glaucoma and cataract. The aims of this study were to quantify aqueous humor Connective Tissue Growth factor (CTGF) in PXF glaucoma, to determine the effect of CTG...

Oxidative stress is implicit in the pathological changes associated with glaucoma. The purpose of this study was to compare levels of oxidative stress in glial fibrillary acid-negative protein (GFAP) lamina cribrosa (LC) cells obtained from the optic nerve head (ONH) region of 5 normal (NLC) and 4 glaucomatous (GLC) human donor eyes and to also exa...

This paper seeks to investigate differences between the neonatal and adult retinal ganglion cell populations to apoptotic death stimuli. DESIGN AND SAMPLES: In vitro and ex vivo paradigms involving P6 and P60 Sprague-Dawley rat retinal explants and retinal ganglion cells were employed.  Postnatal day 6 (P6) and 60 (P60) Sprague-Dawley retinal gangl...

In many retinal diseases, it is the death of photoreceptors that leads to blindness. In previous in vitro and in vivo studies, basic fibroblast growth factor (bFGF) has been shown to increase retinal cell survival. More recently, reactive oxygen species (ROS) have also been shown to promote cell survival, contrary to the traditional view that they...

Pseudoexfoliation (PXF) syndrome is a generalized disorder of the extracellular matrix (ECM) involving the trabecular meshwork (TM), associated with raised intraocular pressure, glaucoma, and cataract. The purposes of this study were to quantify aqueous humor connective tissue growth factor (CTGF) in PXF glaucoma, to determine the effect of CTGF on...

Cyclic stretching of the glial fibrillary acidic protein (GFAP)-negative lamina cribrosa (LC) cell in vitro is associated with transcriptomic changes in genes involved in extracellular matrix (ECM) dynamics in vivo, thereby implicating this cell type in the pathophysiologic changes of the optic nerve head (ONH) in glaucoma. The purpose of the study...

Aberrant retinal blood flow is a hallmark of various retinopathies and may be a causative factor in the pathology associated with these conditions. We examined the effects of pulsatile flow on bovine retinal endothelial cell (BREC) and bovine retinal pericyte (BRP) apoptosis and proliferation. Co-cultured BRECs and BRPs were exposed to low (0.3 mL/...

Complex repertoires of IgG autoantibodies have been detected against ocular antigens in patients with glaucoma. The goal was to identify and characterize the IgG autoantibody repertoires in sera of patients with pseudoexfoliation glaucoma (PXFG) with protein macroarrays. Serum samples of 21 patients with PXFG and 19 age- and sex-matched control sub...

Abstract Purpose: : The pathological features of glaucoma include cupping and pallor of the optic nerve head (ONH) and characteristic visual field loss. Cupping of the ONH is associated with compression and collapse of the lamina cribrosa (LC) connective tissue. Calcium is a key regulator of diverse cellular functions and consequently intracellula...

Supplementary Table 1: Peptide and protein identification. In order to identify proteins present in the collected fractions, each lane from the SDS-PAGE gel of fractionated platelet relaseate was divided into 32 bands, digested with trypsin and subjected to LC-MS/MS. The resulting spectra were searched using SEQUEST against the International Protei...