Hasenin Al-khersan, University of Chicago
Connexin Channell and Hemichannel Function in Cx46fs380 Mouse Lenses
A cataract is a clouding of the lens that impedes light’s ability to reach the retina. Cataracts are the leading cause of blindness in the world. Cataracts can have many causes, and some are genetically inherited. Some of these congenital cataracts are caused by mutations in proteins that allow the cells in the lens to communicate with each other and their environment (connexins). While many such mutations have been identified, the physiological changes caused by these mutations at the cellular level remain largely unknown. Our project aims to study one of these mutations, Cx46fs380, and its effect on cellular communication within the lens. Specifically, we seek to understand how this mutation affects intercellular transport among lens cells, eventually leading to the formation of cataracts. An understanding of how such mutations affect communication and nutrient/waste transport is important. This knowledge can facilitate the development of new medicines for prevention and treatment. Medicinal therapies might avoid the complications of current surgical treatment and provide treatment in countries where surgery is unavailable.
MacKenzie Becker, Loyola University Chicago
Corneal allogroft outcomes in patients with Human Immunodeficiency Virus Infection
Human immunodeficiency virus (HIV) is a virus that infects CD4+ T cells, a critical factor in cell-mediated immunity. Patients with HIV infection and AIDS are prone to the development of many ocular related diseases that affect all segments of the eye. Corneal manifestations of HIV infection and AIDS range from opportunistic infections to sequelae of the viral infection itself such as keratoconjunctivitis sicca and corneal deposits.7 Due to the introduction of HAART therapy, individuals with HIV infection are now living longer than ever before, allowing for more aggressive management of corneal disorders, including corneal transplantation. To date, there is no published data regarding the causes of corneal disease leading to corneal transplantation in HIV infected and AIDS patients. There is also no published data discussing the outcomes of corneal transplantation in AIDS and HIV patients. Several studies in murine models have displayed that mice with CD4+ T cell gene knockout or dysfunction had better corneal graft survival than controls.1,3,6,16,20 This suggests that patients with HIV infection or AIDS may have higher likelihood of corneal graft survival secondary to their acquired CD4+ T cell dysfunction. Our proposed study design is a multicenter, retrospective cohort study that will investigate the rates of corneal graft survival and rejection in HIV positive patients over the past 30 years.
Andrea Blitzer, Edward Hines Jr. Hospital
SiRNA as a Promising Therapeutic Strategy in Regulating Outflow Resistance
Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. POAG is frequently associated with elevated intraocular pressure (IOP), which can lead to irreversible blindness. In healthy eyes, IOP is maintained by balanced production and outflow of aqueous humor (AH). The rate of AH outflow is largely regulated by cells of the trabecular meshwork (TM), a highly specialized tissue within the anterior segment of the eye. AH collected from POAG patients contain markedly elevated levels of transforming growth factor (TGF)-β2, a cytokine that promotes TM cell contraction and decreases AH outflow. Novel translational studies are critically needed to develop advanced therapeutic strategies for the care of patients debilitated by POAG. siRNA technology is an exciting and promising new field that involves the use of short strands of RNA to promote degradation (i.e. “knockdown”) of specific genes before they can be made into functional proteins. In this study, we will determine whether siRNA-mediated knockdown of TGF-β2 signaling proteins can effectively lower elevated IOP by decreasing TM cell contraction.
William Chang, Northwestern University
Biomarkers of Proliferative Diabetic Retinopathy
Diabetic retinopathy (DR) is a major cause of blindness worldwide and is prevalent in roughly 80% of diabetics after having the disease for 10 years. Proliferative diabetic retinopathy (PDR) is the late stage manifestation of DR and is characterized by fibrosis and angiogenesis. This can result in the formation of an epiretinal membrane (ERM) and traction, which can lead to complications such as retinal detachment and vision loss. Currently, the molecular mechanism of ERM formation is not fully understood. Recent studies have shown ERMs and vitreous humors of patients with PDR contain different protein marker patterns than non-PDR tissues. However, the localization of these markers within human ERM tissues has not been extensively studied. We wish to characterize the cellular composition of PDR membranes by identifying and quantifying the amount of fibrotic and angiogenic biomarkers in PDR ERMs. We will use immunohistochemical methods to label these biomarkers in PDR and non-PDR ERMs. Imaging analysis will allow for comparison of PDR and non-PDR ERMs and determination of cellular characteristics unique to the pathophysiology of PDR. Through characterization of the molecular and cellular changes of ERM formation, this study serves to contribute to the understanding of the progression of PDR. The identification of unique biomarkers of PDR can yield targets for therapeutic options to prevent or treat diabetic retinopathy.
Judy Chen, University of Illinois at Chicago
Vision Loss and Papilledema in Patients with Brain Tumors – 2015 James A. McKechie Jr. Award for Proposal Excellence
Brain tumors can cause significant visual changes, both from direct compression of the tumor as well as from indirect effects of elevated intracranial pressure causing papilledema. Papilledema is particularly concerning because it can cause irreversible damage and requires additional treatment distinct from tumor management. Currently, very little is known not only about the prevalence of papilledema in patients with brain tumors, but also how to detect patients at risk for loss of vision from papilledema. The purpose of this project is to establish the prevalence of papilledema in patients with brain tumors and to determine the disease characteristics and symptoms that are associated with papilledema. The results will inform the development of a clinical screening program for papilledema in brain tumor patients and form the foundation for future studies to determine visual outcomes in brain tumor patients with papilledema, as well as to evaluate the effectiveness of papilledema-directed treatments.
Dong-Jin Choi University of Illinois at Chicago
Functional Role of Optineurin in Age Related Macular Degeneration
Age-related macular degeneration (AMD) is a deterioration or breakdown of the eye’s macula, a small area in the retina that responsible for the sharp, central vision needed to read or drive. The pathogenesis, however, is not fully understood. Through extensive studies in the past decades, people found evidences such as oxidative stress plays an important role in AMD pathogenesis; autophagy dysfunction has been implicated in retinal pigment epithelium (RPE) degeneration in AMD; lipid and protein aggregation found in drusen is a indicator of increased risk of the complications of AMD. These evidences are like puzzles with missing pieces for the complete picture of the development of AMD. This proposal aims to identify whether optineurin is a significant contributor to autophagy dysfunction induced by oxidative stress in AMD and subsequent RPE degeneration. Optienurin is a scalfold protein and an autophagy receptor. We will examine the regulation of optineurin under oxidative stress condition both in vitro and in vivo and delineate the relationship between optineurin and RPE pathological phenotypes (autophagy dysfunction, increase of extracellular protein deposit, and apoptosis). Understanding the role of optineurin in AMD pathogenesis will help to design therapeutics to treat this complicate disease.
Matthew Collins, Edward Hines Jr. Hospital
Mitochondrial-specific antioxidant XJB-5-131 attenutes endogenous TGF-B-2 expression in human trabecular meshwork cells
Glaucoma is a leading cause of blindness, projected to affect nearly 80 million people worldwide by the year 2020.1 In the US, it is estimated that nearly 2 million individuals age 45 years and older have primary open angle glaucoma (POAG), the most prevalent form of the disease.2 Indolent in nature, POAG slowly develops into irreversible loss of vision. Current treatment options for patients with POAG are aimed at lowering chronically elevated intraocular pressure (IOP), a poorly-understood risk factor associated with POAG. In healthy eyes, normal IOP is maintained through balanced production and outflow of aqueous humor (AH). In adults, the majority (>50%) of AH exits the eye through the trabecular meshwork (TM).3 While the cause of elevated IOP remains unclear, one possible reason for the buildup of AH may involve harmful production of reactive oxygen species (ROS) within the TM. Despite advancements, the mechanism by which elevated levels of ROS contribute to POAG is not entirely clear. Recent studies suggest that ROS elevate levels of TGF- β2, a cytokine that has been strongly associated with elevated IOP and POAG.4, 5 Here, we will determine whether compound XJB-5-131, a novel mitochondrial-selective antioxidant,6 will alter constitutive TGF-β2 expression and/or signaling in human trabecular meshwork cells.
Daniel Colon, Northwestern University
Early Dectection of Choroidal Neovascularization Using Optical Coherence Tomographic Angiography
Age-related macular degeneration (AMD) causing choroidal neovascularization(CNV) represents the leading cause of vision loss in individuals greater than 55 years old in developed countries. Prompt diagnosis and treatment is essential in order to prevent vision deterioration. Current methods of diagnosis, such as fluorescein angiography are far from perfect as leakage can obscure images and there is a risk of adverse or allergic reaction to the injected dye. Our goal is to provide evidence to support that optical coherence tomographic angiography (OCTA) can be used to diagnose CNV with reliability and accuracy in the asymptomatic high-risk population.
Christy Cunningham, Cook County Health and Hospital
Dietary Effects on Intraocular Pressure Control
Primary open angle glaucoma (POAG) is an optic neuropathy with characteristic visual field changes in which elevated intraocular pressure (IOP) is one of the risk factors. Pharmacologic treatment of the disease is primarily aimed at lowering IOP through the use of ocular hypotensive medications. Both topical and systemic medications have been proven to lower IOP, however little work has been done on how dietary intake can affect IOP control. Our team seeks to investigate whether consumption of MSG, histamine, or fasting would significantly alter IOP measurements. We plan to compare any induced alterations of IOP in participants both with and without POAG to determine the effects of the above dietary intake on IOP. A possible positive correlation between consumption of these substances and IOP control could lead to dietary modifications to be included as a treatment option in patients with POAG.
El Harith Elsiddig, Loyola University Chicago
The pathophysiology of Sleep Apnea and its Association with Ocular Diseases: Floppy Eyelid Syndrome and Diseases of the Optic Nerve
Floppy eyelid syndrome (FES), a subset of a broader group of eyelid abnormalities termed lax eyelid condition (LEC), describes a syndrome of rubbery, lax upper eyelids with tarsal papillary conjunctivitis seen in young obese men. Previous studies have reported the histopathology and proposed pathophysiology of the eyelid laxity. Obstructive sleep apnea (OSA) is characterized by interruption of ventilation for more than 10 seconds due to airway collapse7. The cause of this disorder has been related to obesity, increase in neck circumference and increase in the size of the soft palate and tongue. The exact explanation for the changes in the soft palate and tongue is unclear but some reports demonstrate a decrease in elastin in the soft palate and uvula tissue.
The purpose of this study is to compare the elastin in normal patients with those with OSA in a variety of tissues including: the eyelid, skin, optic nerve, orbit and soft palate. We will also measure the levels of VEGF and assess the degree of vascularization in the same tissues. The hypothesis is that OSA, and the resultant lack of oxygen, leads to a generalized increase in inflammation including enzymes that digest elastin, as well as new blood vessel growth.
William Gange, Loyola University Chicago
Neuroprotection of Nucleoside Reverse Transcriptase Inhibitors on Retinal Ischemia Reperfusion Injury
Retinal ischemia is a common cause of visual impairment and blindness. It is a major contributor to tissue damage in diseases including acute angle-closure glaucoma, diabetic retinopathy, retinal vascular occlusions and retinopathy of prematurity. IR-injury often leads to initial neuron cell death, followed by retinal inflammation, further tissue damage, and eventually retinal dysfunction. Treatment for retinal ischemic diseases is very limited. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) were the first drugs to receive federal approval for the treatment of HIV/AIDS in the late 1980s. Recently, it has been reported that the NRTIs block a type of inflammasome called NLRP3 and prevent retinal degeneration in a mouse model of age-related macular degeneration (AMD). In this study, we propose to determine the neuroprotective effects of NRTIs on retinal ischemia in vivo. We will investigate if NRTIs mediate neuroprotective effects against retinal ischemia-reperfusion injury in mice as quantified structurally and functionally. This study will advance our knowledge in developing therapies against retinal ischemic degeneration diseases.
Stephens Holland, Loyola University Chicago
Elucidation proteomic mechanisms promoting cell survival subsequent to red light and near infrared therapy for the prevention of retinal degeneration – 2015 AMD Research Award
Age related macular degeneration (AMD) is complex disorder of older adults related to the death of retinal cells that often leads to significant visual disability. As with any disease entity, prevention and disease risk reduction are critical elements in preventing permanent disability. Unfortunately, preventative strategies for AMD are few in number. Vitamins and nutrients may be of help, but only in select patient populations. One promising preventative treatment alternative we are examining is the use of non-drug related red and near infrared light therapy. Red light and near infrared therapy has been found to be highly effective in reducing injury of the retina due to light exposure and exerts a pronounced healing effect on various types of tissue injury. This study will provide important information regarding how light therapy works to prevent retinal degeneration. We will examine the genetic effects of red light and near infrared treatment and determine how this treatment exerts its beneficial effect at the cellular level.
Paul Gerard O’Malley, Loyola University Chicago
Association of Polumorphism of vascular endothelial growth factor and catechol-o-methyltransferase in age related macular degeneration in American Population
Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the elderly population with an estimated $98 billion USD healthcare expenditure in the United States & Canada $255 billion globally. To simplify, AMD is of two types, the wet and dry form. The central portion of the inner layer of the eye, the retina, which is responsible for the vision develops a degenerative condition resulting in blindness. This affects the daily activities and strongly impacts the functional status and quality of life in these patients. The mechanism of how this disease is caused or initiated is not fully understood. Impaired blood supply (ischemia), hypoxia and adverse effects due to hypoxia (oxidative stress) and the secretion of some growth factors (Vascular Endothelial Growth Factor – VEGF) which promote the growth of new blood vessels may play an important role in the causation of this disease process. The risk factors for AMD are heterogeneous and may include age, genetic predisposition,several environmental and epigenetic factors. A large-scale longitudinal population based study (The Beaver Dam Eye Study) concluded that regular and chronic use of aspirin was associated with AMD. The aim of this study is to determine the variants (polymorphisms) of genes responsible for the secretion of VEGF and of Catechol-O-methyl transferase (COMT) in AMD patients who were either receiving or not receiving aspirin.
Rima Patel, Loyola University Chicago
Changes in the Pevelance of Lax Eyelid Condition (LEC) Lax Eyelid Syndrome (LES) and Floppy Eyelid Syndrome (FES) in Patients Following Bariatric Surgery
Floppy eyelid syndrome (FES) was initially described in 1981, with the typical phenotype being that of an obese middle-aged male (1). FES has been described as an entity composed of rubbery, floppy upper eyelids associated with palpebral conjunctivitis of the upper lid by (2). Lax eyelid condition (LEC) alone and lax eyelid syndrome (LES) associated with chronic conjunctivitis have also been reported without the association of obesity and male gender (3). The prevalence of FES in obesity is known to be high, and is a component of the definition of FES (2). Beis et. al attempted to identify a relationship between obesity and FES, but no association was found (4), even though obesity affects the vast majority of patients with FES. FES has also been associated with obstructive sleep apnea (OSA) (5). OSA is a well-defined condition with multiple significant comorbidities. It is estimated that there are 19 million patients in the US with undiagnosed sleep apnea (6). Based on our clinical experience, the association between FES, obesity and OSA is higher than what has been previously reported, and the prevalence of FES and OSA in obese patients may be significantly decreased by bariatric surgery. Identifying an association between 1) the presence and 2) severity of LEC, LES, FES, OSA and obesity would provide valuable diagnostic signs for identifying patients at risk for OSA. Furthermore, the demonstration of improvement in OSA and a change in the severity of FES following bariatric surgery would provide important support for reducing the morbidity associated with obesity.
Joseph Simonett, Northwestern University
Adaptive Optics Imaging of Micro-aneurysms and Photoreceptor in Layer in Early Diabetic Retinopathy and Predictors of Disease Progression
Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus (DM) and the leading cause of blindness in the working-age population in the United States. Early pathologic changes, including microaneurysms (MA) and subclinical retinal ischemia, often go undetected as vision is typically preserved. Development of vision threatening complications, including retinal bleeding, swelling and abnormal blood vessel growth, follow progression of these early microvascular changes, but little is known regarding why some progress while others stay quiet. A major limitation of studying microvascular and cellular level changes has been their miniscule sizes and our inability to image with the necessary resolution in the living eye. Emerging adaptive optics (AO) retinal imaging techniques, which compensate for ocular wavefront aberrations and greatly improve imaging resolution, allow for highly detailed, noninvasive in vivo study of retinal microvascular changes and photoreceptor density.1 In our study, noninvasive AO imaging will be used to measure and characterize MAs, grade MA internal blood flow turbulence, and measure photoreceptor density in patients with early DR (Figure 1 and 2). Findings will be correlated with disease progression and need for treatment at 6 and 12 month follow-up visits. As preventative DR treatment advances, identification of MA rupture or leakage risk characteristics, related to dimension, morphology and fluid dynamics, is becoming increasingly valuable. Furthermore, identification of AO imaging findings that correlate with DR disease progression may allow for selection of early intervention candidates.
John Thompson, Loyola University Chicago
Assessing Ocular Microbiome Diversity in Stevens-Johnson’s syndrome
Stevens-Johnson’s Syndrome (SJS) and toxic epidermal necrolysis (TEN) are part of a continuum of life-threatening severe allergic reactions that affect the skin and mucosal surfaces including the eye. This disease can result from a genetically predisposed reaction to either infection or medications. Both conditions are associated with the separation of the top layer of skin (the epidermis) from the layer underneath (the dermis), resulting in blister formation on the skin and severe inflammation on the ocular surface that can result in significant scarring and blindness. Loss of skin integrity predisposes these patients to severe infections, which account for a high mortality rate of 25% to 50%. Patients who do recover from this disease often suffer from lifelong eye complications, chronic inflammation and severe visual loss. Although there have been studies assessing the microbial population on healthy eyes, there has been no study reporting the changes to the microbiome during SJS/TEN. Our study will provide important and valuable information about the changes that occur within the microbiome in both the acute and chronic stages of this severe ocular surface disease. Identification of changes in the microbiome may lead to better treatment options for SJS/TEN, reducing the high rate of infection, chronic scarring and subsequent blindness.
Yougang Zhai, Loyola University Chicago
The Role of TRPM2 in age related macular degeneration
Age-related macular degeneration (AMD), a multifactorial disease, is a leading cause of visual impairment and blindness in the developed countries. Approximately 1.7 million Americans have some form of AMD, and approximately 100,000 suffer vision loss from AMD. Presently, treatment for advanced AMD is very limited. The mechanism of this disease is not fully understood. Impaired blood supply (ischemia), low supply of oxygen, adverse effects due to low oxygen (oxidative stress), and the secretion of some growth factors (Vascular Endothelial Growth Factor – VEGF) which promote the growth of new blood vessels may play an important role in this disease process. Recently, studies have highlighted the critical role of the inflammatory process called “NLRP3 inflammasome” in AMD. This inflammatory process is associated with oxidative stress and subsequent cell death of retinal pigment epithelium (the cells are important for vision). In this study, we will investigate the mechanism of “NLRP3 inflammasome” activation and test inhibitors for this activation by using in vitro cell culture model. This study will advance our knowledge in developing mechanism-based therapies against age-related macular degeneration.