Role of Inflammation in Keratoconus
Keratoconus is a chronic, predominantly bilateral, non-inflammatory primary ectasia associated with irregular astigmatism and decreased visual acuity. Eventually, it can lead to thinning, scarring, and protrusion of the cornea. Although the pathogenesis is not fully understood, it is hypothesized that oxidative stress plays a role in the corneal remodeling that occurs. This study aims to study the mechanism of mitochondrial dysfunction in human corneal endothelial, epithelial, and stromal cells. Additionally, activation of the TGFβ signaling pathway has been shown to play a role in the development of keratoconus. Blockade of this pathway via Smad3 inhibitors may provide an effective alternative treatment. This study aims to study the effects of TGF-beta 2 expression when exposed to TNF-α with or without a Smad3 inhibitor (SIS3) in human corneal epithelial, stromal and endothelial cell cultures.
The Therapeutic Effect of Bacterial Exopolysaccharides on Experimental Dry EyeDry eye disease (DED) is a disorder that results in symptoms of eye irritation, blurred vision, eye dryness, and overall discomfort. It is characterized clinically by inflammation that affects the ocular surface, and in more severe cases can lead to blindness. Multiple studies have shown increased expression of a protein called toll-like receptor 4 (TLR-4), which contributes to the inflammation seen in DED. Exopolysaccharide (EPS) is a bacterial component of B. subtilis, which has been shown to protect against intestinal inflammation by working against TLR-4. This study will investigate the effects of EPS on DED using an experimental dry eye mouse model.
Conversion to Aflibercept for Diabetic Macular Edema Unresponsive to Bevacizumab in Cook County Hospital System
Diabetic macular edema (DME), defined as thickening of the retina responsible for central vision, is the most common cause of visual impairment in patients with diabetes. Recently, there have been significant advances in the management of DME and the three different anti-Vascular Endothelial Factor (anti-VEGF) agents (Bevacizumab, Ranibizumab and Aflibercept) are the mainstay of treatment of DME.
Chicago’s Cook County Health and Hospital System (CCHHS) is one of the largest public county hospitals in the USA, serving a large distinct diabetic patient population consisting mostly of African Americans and Hispanics representing a unique subset, unrepresentative of the general population. Limited data are available regarding visual and anatomic outcomes of conversion to aflibercept for DME unresponsive to bevacizumab, particularly in the diabetic patient cohort with demographics seen in a County public hospital health system.
This study intends to investigate if eyes with DME not adequately controlled with bevacizumab would benefit from conversion to aflibercept in the unique diabetic population at CCHHS.
Color Contrast Sensitivity in Non-Exudative Macular Degeneration
This study will determine whether differences exist in color contrast sensitivity in dry age-related macular degeneration (AMD) patients. Two groups will be enrolled: study group consists of subjects with dry AMD and a control group. Each eye will be tested using King Devick Color Contrast Acuity Test. Vision is assessed using 100% contrast with black letters; then using red, green, blue, and yellow. The test will be repeated at decreasing levels of contrast. We hypothesize that blue color contrast sensitivity may be affected earliest. This test may potentially detect subtle disease changes over time prior to more severe vision loss.
Fluorophotometric Measurement of the Precorneal Residence Time of Topically Applied Sodium Fluorecein Based on Drop Volume
The treatment of ocular disease commonly relies on eye drops. Commercial bottles deliver only one volume thus treatment is limited to a fixed drug dose. Furthermore, drop volumes are often delivered in excess which causes spillage and dilution of the drug from increased tearing. Small eye drop volumes could enhance the availability of the drug by decreasing tearing, thereby lengthening the amount of time the drug stays in the tear film. The purpose of this study is to determine if reduced eye drop volume minimizes effects on tearing in both normal and dry eye patients as measured by fluorophotometry.
Impact of Cataract Surgery in Patients with Low-Tension Glaucoma in a University Setting
Glaucoma is a multifactorial, progressive disease that leads to optic nerve damage and associated visual field loss. Elevated intraocular pressure (IOP) is a primary risk factor for glaucoma development. However, even patients with untreated IOP in the normal range can develop glaucoma. This is termed low-tension glaucoma (LTG). Studies have shown that further reduction in IOP decreases glaucoma progression even in LTG. Given that cataract surgery has been shown to decrease IOP in glaucoma patients, we are interested in evaluating the impact of cataract surgery specifically in LTG patients.
Corneal Ectasia Associated with Post-Operative Hypotony in Glaucoma Surgeries
Ocular hypotony is a common complication after glaucoma surgeries. In the tube versus trabeculectomy (TVT) study, persistent hypotony accounted for 13% of treatment failures in the tube group and 31% of failures in the trabeculectomy group. The occurrence of corneal ectasia and hydrops have been described previously to occur in the setting of ocular hypotony. However, patterns of corneal topographical changes in the setting of ocular hypotony related to glaucoma surgeries is currently unknown. Our preliminary data suggest that corneal ectasia and topographical changes occur in hypotonous eyes after glaucoma surgeries. This study intends to describe the effect of hypotony related to glaucoma surgeries on corneal topography. Recognizing this potential complication and prompt treatment will prevent permanent damage to the cornea and visual loss.
Alzheimer’s Disease and Super Agers Changes in the Eye
Early diagnosis of Alzheimer’s disease remains a highly sought after but elusive goal. Funded by the ISPB, we have recently found an inverse correlation between cognitive function and retina thickness using optical coherence tomography in amnestic mild cognitive impairment (aMCI) subjects. This finding could be related to the development of scarring in the inner retina. We are therefore now using advanced imaging technologies to examine for scarring on the surface of the retina in aMCI subjects. In addition, we are extending the study to include SuperAgers, a distinct population with cognitive abilities comparable to subjects that are 2-3 decades younger.
Elevated Hydrostatic Pressure Alters Endogenous Expression of CTGF, ET-1 and TGF-β2 in Human Trabecular Meshwork Cells
Glaucoma is a leading cause of blindness worldwide, projected to affect nearly 80 million people by the year 2020. 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. Although the pathophysiology of POAG remains unclear, elevated intraocular pressure (10P) is considered a poorly-understood hallmark in most patients with POAG.
Within healthy eyes, 10P is maintained by a balance of aqueous humor (AH) production and outflow. In patients with POAG, increased AH outflow resistance is considered a major contributor to pathologically elevated 10P.
Transforming growth factor (TGF)-β2, a pro-fibrotic cytokine present within AH, is markedly elevated in some patients with POAG. We and others have previously shown that TGF-β2 enhances outflow resistance and increases 10P, in part, by inducing endothelin-1 (ET-1) and connective tissue growth factor (CTGF) expression and release within the TM. ET-1 and CTGF may ultimately lead to increases in 10P by enhancing TM cell contractility and extracellular matrix (ECM) deposition.
Despite these advancements, the direct effect of elevated pressure on TM cell responses remains unknown. Here, we present preliminary findings showing that cultured TM cells exposed to elevated hydrostatic pressure exhibit marked increases in endogenous CTGF, ET-1, and TGF-β2 expression and release, possibly involving the activation of mechano-sensitive ion channels.
The NLRP3 Inflammasome Activation and Diabetic Dry Eye
Diabetic ocular complications have been a leading cause of blindness in the world, including diabetic retinal disease, cataract, and various ocular surface disorders including dry eye. The pathogenesis of diabetic dry eye is not fully understood; however, the inflammation has a prominent role in the development and amplification of the signs and symptoms of dry eye. Recently, it has been reported that NLRP3 is expressed in human conjunctival and corneal epithelial cells; as a ROS sensor, NLRP3 inflammasome activation and further maturation and activation of casepase-1 and IL-1β processes are a prerequisite for dry eye initiation and progression. In this project, we will investigate if activation of NLRP3 inflammasome play an important role in diabetic dry eye inflammation and inhibit NLRP3 inflammasome activation will improve the diabetic dry eye inflammation. The proposed study will provide novel insights into potential therapeutic interventions for the treatment of diabetic dry eye.
New Theory for the Cause of POAG
Primary open-angle glaucoma (POAG) is a common blinding ocular disease without a known cause. Recently, one possible cause for the disease was proposed known as the multiple hit theory of POAG. The first hit is damage to the fenestrated capillaries of the ciliary body (which produces aqueous humor) leading to cell death in the ciliary body. As the ciliary body is damaged, toxic byproducts are released into the aqueous and these proteins then cause cell death in the filter of the eye, the trabecular meshwork, leading to increased eye pressure. The second hit is damage to the fenestrated capillaries of the choroid plexus (which produces cerebrospinal fluid) leading to cell death of the choroid plexus. This, in turn, decreases cerebrospinal fluid production, and subsequently decreases brain pressure. The third hit is the combination of increased eye pressure and decreased brain pressure, resulting in translaminar damage to the optic nerve fibers.
Early Inner-Retina Dysfunction in Diabetic Retinopathy
Diabetic retinopathy (DR) is a leading cause of blindness in the United States. Although DR is typically defined by changes of the retinal vasculature, mounting evidence suggests inner-retina neural abnormalities occur prior to clinically-apparent vascular changes. However, functional abnormalities of the inner-retina are poorly understood. In this study, two measures of inner-retina function will be obtained from diabetic patients who have minimal or no clinically-apparent diabetic retinopathy (M/N DR): 1) pupil responses to flashes of light; 2) electrical responses of the inner-retina to patterned stimuli. These measurements will permit quantifying functional deficits in patients with M/N DR, leading to the development of biomarkers that will be essential for future clinical trials.
Structure-Function Relationship of Retinal Capillary Non-Perfusion in Three Capillary Plexuses
Optical coherence tomography angiography (OCTA) is a rapidly evolving imaging modality that is used to visualize blood flow within retinal vessels in three distinct capillary networks. Patients with diabetic retinopathy can show retinal vascular compromise such as capillary non-perfusion that can lead to ischemia in the retina. Areas of capillary non-perfusion in the three different capillary networks found on OCTA will be correlated to structural changes in retinal tissue to explore the relationship between retinal ischemia and tissue structure. This project will provide a better understanding of how ischemia in the retina impacts tissue structure in the retina.
Paeoniflorin Protects Against Retinal Degeneration in an Animal Model of Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is a leading cause of blindness in the United States and other developed nations. Current treatments targeting AMD are beneficial to only a small proportion of patients and do not necessarily prevent progression of the disease. Paeoniflorin is a main active component of Paeonia Radix, a traditional Chinese herbal medicine, and possesses both anti-inflammatory and anti-oxidant properties. We predict that paeoniflorin will have protective effects against retinal degeneration in a mouse model of AMD by reducing the inflammatory response and oxidization levels and prove to be a viable and novel potential therapeutic against this vision-threatening condition.
Results of a Novel Glaucoma Treatment: Micropulse Transscleral Cyclophotocoagulation Diode Laser
Glaucoma is the leading cause of blindness worldwide, and 7.3 million patients are expected to be affected in the United States by 2050. Current treatments options for glaucoma include eyedrops, lasers, and incisional surgery. A new glaucoma laser called micropulse transcleral cyclophotocoagulation (MP-TSCPC) has recently come into practice for treatment of glaucoma refractory to medications. Little is known about the safety profile of the laser, its long-term pressure modifying effects, or its mechanism of action. Our study aims to determine the side effects and mechanism of action of the laser to determine the ideal patient population for the laser.
Calcium Signaling in Exfoliation Glaucoma
Exfoliation glaucoma is a severe form of glaucoma that can ultimately result in complete loss of vision. It is known that genetic factors can predispose to exfoliation glaucoma, however, the molecular mechanisms leading to the full blown disease are still unknown. Our laboratory is investigating a novel hypothesis of how an individual’s genetic makeup can cause exfoliation glaucoma. Specifically, we are studying how genetic factors alter communication within and between cells. Identifying broken chains in cellular communication will help us devise novel therapies for treating exfoliation glaucoma and, thereby, help improve the lives of those affected by this blinding disease.
Incidence of Massive Submacular Hemorrhage in AMD in Patients on Anticoagulation
Macular degeneration is a disease of the retina that can cause permanent blindness in the elderly. People with advanced macular degeneration can sometimes have devastating bleeds in the area of the retina responsible for central vision, the macula. Many older Americans have medical conditions that require the chronic use of blood thinners. Some retina specialists have anecdotally noticed an increase in macular bleeds in patients with macular degeneration who are taking blood thinners, especially the new blood thinners on the market. Our study is aimed at determining whether these new blood thinners lead to increased rates of bleeding in macular degeneration as compared to warfarin, the previous blood thinner of choice.
Brian Soetikno, Northwestern University
Enhancing Interpretation of Optical Coherence Tomography Angiography in Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is a leading cause of blindness in people 50 years of age or older in the United States. Optical coherence tomography angiography (OCTA) is a novel imaging modality, which provides three-dimensional, contrast-free imaging for the diagnosis and treatment of AMD. This project seeks to improve the clinical interpretation of OCTA by developing novel software algorithms which will enhance visualization of important structural markers in OCTA images. Ultimately, this advance will benefit clinicians, by easing the interpretation of OCTA, and will benefit patients, by preventing the misdiagnosis of AMD.
Mechanisms of Retinal Ischemic Post-Conditioning
Eye diseases such as diabetic retinopathy and glaucoma result in vision loss. No effective treatment is available thus far, so it is our goal to repair retinal ganglion cells and prevent further damage. In our previous work in rodents, we reported that post-conditioning (Post-C, short ischemic insult 24 h after ischemia) can effectively protect the retina from further injury. In this study, we will examine the hypothesis that multi-signaling mechanisms work in synchrony to produce post-C. The results will enable us to selectively activate multiple signaling pathways to replicate the neuroprotective effects of post-C, and offer hope of clinical treatment.
The Role of Ubiquilin 2 in Age-Relation Macular Degeneration
This proposal aims to investigate drusen, abnormal aggregations which build up in the retina in age-related macular degeneration (AMD), and ubiquilin 2, an important component of the sub-cellular system responsible for breaking down damaged components of cells. Ubiquilin 2 has never been studied in the eye or AMD. We will investigate ubiquilin 2’s function in the retina using tissue samples from AMD patients and age-matched controls. Our studies will address an important gap in our understanding of AMD and may open promising new avenues for research which could lead to new treatments to delay or prevent the progression of AMD.
The Association Between Ocular Surface Inflammation and Cornea Thinning
Obstructive sleep apnea is a disease process that affects a large proportion of the US population. Estimates of disease prevalence for sleep apnea range from 3% to 7%. Moreover, sleep apnea is a disease process that is known to have multiple manifestations in the human eye, including, but not limited to worsening floppy eyelid syndrome, ocular surface inflammation, papilledema, diabetic retinopathy, and retinal vein occlusion. A recent study conducted by researchers at Kellogg Eye Center at the University of Michigan has demonstrated that sleep apnea and asthma are two conditions that are significantly associated with the development of keratoconus, in addition to the previously described well-known risk factors of hispanic race and Downs syndrome. Keratoconus is a disease that is defined as a progressive, conical protrusion and thinning of the central part of the cornea, resulting in an irregular astigmatism (of the corneal surface) that can cause significant vision loss. While the link between sleep apnea, corneal thinning, and keratoconus has been clearly identified, the mechanisms underlying this association remain nebulous. Recently, multiple research groups have begun to define the molecular factors and the associated systemic conditions that are associated with corneal thinning. Furthermore, specific studies have demonstrated that sleep apnea is associated with corneal thinning, and the degree of corneal thinning correlates with the severity of the sleep apnea. This grant will attempt to better define the relationship between sleep apnea, corneal thinning, and keratoconus by further characterizing corneal thinning in patients with known sleep apnea using high resolution anterior segment OCT. We will seek to further elucidate the association of ocular surface inflammation and corneal thinning in our sleep apnea patient cohort by characterizing the degree of surface inflammation in our sleep apnea patients. Overall, the study will seek to better establish the relationship between sleep apnea, ocular surface inflammation, and corneal thinning.
The Roles of IL-33 and TGF-β in the Pathogenesis of Acute Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a disease continuum of potentially life threatening, severe allergic drug reactions which result in apoptosis (programmed cell death) of cells in the skin, mucous membranes, and ocular surface. The exact pathophysiological mechanisms leading to this apoptosis is unclear but genetic predisposition and abnormal immune regulations play a role. Interleukin-33 (IL-33) and transforming growth factor beta (TGF-β) are known to be involved in many inflammatory and apoptotic diseases of the skin, but their roles in SJS/TEN remain unexplored. In the current study we will use immunohistochemistry to investigate the presence of IL-33 and TGF-β in plasma and skin biopsy specimens of patients with SJS/TEN. The results of our study will enhance our understanding of the pathogenesis of SJS/TEN and potentially suggest potential therapeutic strategies against this disease.
Shuangyoung Wang, PhD, University of Illinois at Chicago
MMP14 Mediate Corneal Neovacularization to Effect the Graft Rejection
Corneal diseases, caused by inflammation or trauma, are the second major cause of blindness. Corneal transplantation is the only effective method for treating corneal blindness, and approximately 40,000 transplantations are being performed each year. Unfortunately, graft rejection is a serious problem that leads to transplant failure. One of the most significant risk factors for graft rejection is corneal neovascularization (i.e., the formation of blood and lymphatic vessels in the normally avascular cornea). Matrix metalloproteinase 14 (MMP14) is usually co-localized with vascular endothelial growth factor receptor (VEGFR) on the vessel endothelial cell membrane and interacts with VEGFR to mediate neovascularization. We will investigate the effects of MMP14 on corneal neovascularization and graft rejection as well as the underlying mechanisms.
Millions of people worldwide are visually impaired. The American Foundation for the Blind reports that only 34% of working age adults who are legally blind are employed. One barrier to employment is the ability to read print. The ORCam is a new spectacle mounted camera device that can speak to the user what the camera is pointing to. For example users can point their ORCam glasses at the newspaper, take a picture using the device and it will read the newspaper to them. This device can also be taught to recognize a known person’s face in order to tell the user who is approaching them and product recognition. The device offers opportunities to its users to be more functional and independent despite their loss of vision thus increase the possibility of employment. While this device is commercially available no studies have looked at which low vision patients benefit most from this device. This pilot project will help eye care practitioners to identify which patients with vision loss are best suited for the device and when to consider recommending it. Co-investigator on this project is Zory Stoev, O.D.