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«Frederick T. Collison, O.D. Chicago Lighthouse for the Blind Treatment of Peripheral Retinoschisis in X-Linked Retinoschisis with Topical Carbonic ...»

Frederick T. Collison, O.D.

Chicago Lighthouse for the Blind

Treatment of Peripheral Retinoschisis in X-Linked Retinoschisis with

Topical Carbonic Anhydrase Inhibitors

X-linked retinoschisis (XLRS) is a retinal dystrophy characterized by

cystic splitting of the retinal layers in the macula, and sometimes in

the peripheral retina. Carbonic anhydrase inhibitor (CAI) eye drops reduce the

central retinal cysts in some patients with XLRS. We observed resolution of mid-

peripheral retinal fluid on spectral domain optical coherence tomography (SD-OCT) in a patient with XLRS treated with a topical CAI. No cases of medical treatment of intraretinal fluid outside the macula in XLRS have been published. We will investigate the effect of CAIs on peripheral retinoschisis by performing pre- and post-treatment SD-OCT and visual field testing.

Julia Malalis, M.D.

Loyola University Chicago Role granulusin and other inflammatory mediators in the pathogenesis of the ocular surface in Steven-Johnson Syndrome and tocis epidermal necrolysis Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are potentially fatal immune-mediated diseases triggered by infections or medications that can lead to devastating ocular surface damage and blindness. Acute inflammation from specific mediators may contribute to the chronic problems associated with these diseases. No report has studied the molecular composition of the ocular discharge that may play a role in the ocular complications in these patients. We will analyze the composition of eye discharge, mouth swabs, skin blisters, blood, and skin biopsies of patients with SJS or TEN in order to better understand how these diseases cause ocular surface damage.

Hajirah Saeed, M.D.

Clinical Signs, Disease Progression, and Possible Hereditary Patterns of Pellucid Marginal Degeneration in Patients and Their family members A genetic basis for various corneal diseases has been identified in recent years.

Hereditary patterns have been found in keratoconus (KC) and may imply a similar pathogenesis for other non-inflammatory corneal ectatic diseases, including pellucid marginal degeneration (PMD). PMD is often misdiagnosed as KC. In contrast to KC, PMD is less common and is distinguished by a band of thinning of the inferior cornea and corneal protrusion superior to this band. No genetic association has been found and/or researched in PMD.

The purpose of this investigation is to elucidate the clinical signs, disease progression, and possible hereditary patterns of PMD in patients and their family members.

Andrea Birnbaum, M.D. PhD Northwestern University Genotype analysis of patients with idiopathic uveitis and a family history of inflammatory bowel disease Uveitis is responsible for 10% of blindness in young adults in the Western world, and chronic uveitis is the most common intraocular manifestation of inflammatory bowel disease (IBD). We have observed that many patients with idiopathic uveitis and a family history of IBD have particular genetic abnormalities known to be associated with IBD. We will test family members of uveitis patients with these mutations who do not have uveitis or IBD to determine whether they also possess similar mutations. If these family members do not have the mutations, this suggests that these genetic abnormalities may be markers specific for disease activity.

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Characterization of Retinal Degeneration in Ocular Hypertensive Mice by ERG Glaucoma, characterized by retinal ganglion cell death, is a leading cause of blindness in the US. Unfortunately, it is not well understood how visual deficits arise with ganglion cell degeneration. Using a mouse model of ocular hypertension to mimic human high-tension glaucoma, we propose to characterize when retinal dysfunction becomes detectable and whether certain areas of the retina are vulnerable to the insult of glaucoma by electro-retinogram (ERG). Our study will thus provide valuable insights on how visual impairments progress and a potential time window for the early detection of the subsequent vision loss in glaucoma patients.

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Diabetic retinopathy (DR) is a leading cause of blindness. Currently, there’s poor understanding of the hemodynamic changes in early DR.

Streptozotocin-induced diabetic rats will be used to characterize the early changes.

These rats develop cataracts as early as 6-weeks, which interfere with optical visualization. A topical aldose reductase inhibitor will be used to delay cataract formation. This project will lay the foundation for future quantitative measures of oxygen consumption in retinal tissues. By better understanding the early metabolic derangements, this study will provide better understanding of early changes in DR and identify potential new targets for therapeutic interventions.

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Role of Forkhead transcription factor in retinal angiogenesis New blood vessel growth in age-related macular degeneration is a major cause of retinal blindness in the aging population and age related macular degeneration. Current treatment approaches are focused on antagonizing a single factor that controls growth of new blood vessels, vascular endothelial growth factor. In collaboration with Dr. Tom Kume in cardiology, we plan to explore a newly described transcription factor that may have a major role in angiogenesis. Our hope is to identify potential new targets for therapy of the wet form of macular degeneration.

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Diabetes is a leading cause of blindness and is commonly associated with corneal epithelial defects. Recently, we discovered that EphA2 receptor tyrosine kinase and ephrin-A1 ligand signaling complexes are disrupted in diabetic corneas. We propose to study the EphA2/ephrin-A1 signaling pathway using a human corneal epithelial equivalent culture model that mimics the hyperglycemic conditions of diabetes. Successful completion of these studies will provide new insight into the pathogenesis of diabetic keratopathy using a novel 3-D culture model for human cornea and determine the feasibility of therapeutically targeting the EphA2/ephrin-A1 axis to restore corneal epithelial homeostasis in patients.

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Mutations in Complement Factor H (CFH) and Age-Related Maculopathy Susceptibility protein 2 (ARMS2)/ high temperature requirement factor A1 (HTRA1) genes were associated with AMD risk and protection. Despite these advances, we do not yet have a clear understanding of how these genes interact or affect risk of progression to advanced AMD. This study will use existing genetic and clinical data in a subgroup of AMD patients at Northwestern University to determine whether certain AMD appearances identified on clinical examination correlate to specific genetic patterns. We will study the role of genetics in defining disease pattern and risk for progression.

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Age-related macular degeneration (AMD) is the leading cause of blindness among ageing Americans. Both the pathogenesis and treatment of AMD are believe to strongly associate with the choroidal vascular system, whose role is still poorly understood. As a result, the capability to image choroidal vascular network with high spatial resolution in vivo becomes essential. None of established modalities is able to image the choroidal vascular network with high spatial resolution and high contrast. In this project, we proposed to develop an indocyanine green assisted photoacoustic ophthalmoscopy for high-resolution and high contrast choroidal vascular network imaging.

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The cornea is physiologically avascular. In certain inflammatory, infectious, degenerative, and traumatic states, the cornea may lose its transparency and a surgical intervention of corneal transplantation is required. However, corneal transplantation may be complicated by rejections, which are mediated by corneal angiogenesis and lymphangiogenesis. We have characterized endostatincontaining fragments that inhibit bFGF-induced corneal angiogenesis and lymphangiogenesis. To further characterize the inhibitory effects of endostatin peptides, we propose to determine the binding properties of endostatin-derived peptides to VEGF receptor 1, 2 and 3 in vitro. This research will lead the way to therapeutic interventions in the treatment of corneal transplant rejection.

Joelle Hallak, MS

BDNF Polymorphism in Dry Eye Disease and Depression

Dry eye affects millions of Americans who suffer from symptoms of eye discomfort such as pain, irritation, and grittiness. Symptomatic dry eye patients also have depressive and anxiety disorders. While investigating the molecular basis of symptoms in dry eye disease in our laboratory, we discovered that BDNF may be an important molecular player. BDNF polymorphisms, such as VAL66MET, also play a significant role in susceptibility of an individual to stress disorders. We hypothesize that this mechanism may also be operational in dry eye patients who have BDNF polymorphism VAL66MET making them more prone to symptoms of depression and dry eye.

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The ability to read is a prevalent concern among patients with vision impairment. Electronic magnification is often needed to meet their goals, and having a better understanding of reading preference and performance with certain devices will aid clinicians in their recommendations. The use of such devices is capable of preventing functional blindness for several individuals with ocular disease. The purpose of this research is to compare an Optelec Clearview CCTV (closed circuit television) and a third generation Apple iPad. A within subject design will be used to compare personal preference as well as an objective measure of reading rate for each patient. Patient age, ocular diagnoses, best corrected distance and near visual acuities (VA), technology use, and preferred source of information will be collected. Only patients eighteen years and older, distance VA between 20/50 and 20/200, and no greater than five hours previous use of a CCTV or iPad in the last two years will be included. The expected results are for preference to correlate to the level of visual impairment. Patients with a greater degree of visual impairment are expected to benefit more from the larger screen of the CCTV, while patients less affected by screen size due to a lesser degree of visual impairment may prefer reading on the iPad, which offers portability and greater social acceptance.

Behrad Y. Milani, M.D.

Gene and mutation identifcation in the Knobloch syndrome, an entity combining neural tube defects, congenital high myopia and childhood retinal detachment To increase understanding of the Knobloch syndrome, an autosomal recessive syndromic developmental connective tissue disease leading to congenital high myopia, an anomalous macula and nystagmus; dislocated lenses, cataracts, and childhood retinal detachments result in irreversible blindness for the majority of patients during their adult years. Two causative genes have been described, COL18A1 and ADAMTS18. We plan to assess the relative frequency of mutations in the two genes in eleven patients from five families. We will correlate the clinical findings and natural history of patients with mutations in either gene.

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HSV-1 keratitis is believed to be the leading cause of infectious blindness in the developed world. Main treatments for this disease have not changed for some time leading to concern over the development of resistance. We will investigate a novel targeted therapy approach to HSV-1 keratitis using a tissue culture model. Cell culture observations that HSV-1 infected cornea cells demonstrate higher cell surface expression of HSV-1 entry co-receptor, heparan sulfate (HS), will be verified in cultured corneas. We will then use novel peptides that bind HS to demonstrate HSVinfection can be blocked in infected corneas.

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Delivery of Active Matrix Metalloproteinase-3 Using Microparticles Elevation of the intraocular pressure in primary open angle glaucoma is believed to be related in part to accumulation of extracellular matrix (ECM) materials in the trabecular meshwork (TM). Current proposal aims to reduce the accumulating ECM materials and to bring the pressure back to normal levels in the TM system by a slow sustained release of active matrix metalloproteinase-3 encapsulated within microparticles. The goals are to optimize conditions for encapsulation, monitor the release, and evaluate the effect of the release on the ECM in human TM cell cultures and on the pressure in a special perfusion organ culture system.

Hongyu Ying, M.S.

Indentification of miRNAs that Regulate the Expression of Myocilin, a Glaucoma Gene Glaucoma is a major blinding disease. The most common form of this disease, primary open angle glaucoma (POAG), is highly heterogeneous, caused by several susceptibility genes and perhaps also environmental factors. Myocilin is the first candidate gene identified for POAG.

Many mutations of myocilin have been found in glaucoma patients. MicroRNAs (miRNAs) are short ribonucleic acid (RNA) molecules that are regulators for expression of genes. Our study aims to identify specific miRNAs that regulate the expression of myocilin. The new information gained may be used to silence myocilin mutants and to develop novel therapeutic modalities for myocilin glaucoma.

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Glaucoma is a major eye disease and leading cause of blindness worldwide. Unfortunately, current visual function assessment methods are insufficient for early detection of glaucoma. It has been shown that glaucoma affects retinal ganglion cells in the parvocellular and magnocellular pathways and, therefore, will lead to impairment in contrast processing functions in these pathways. In this study, we will use novel stimuli in psychophysical paradigms that effectively allow independent assessment of glaucomatous deficits in contrast processing functions in the two pathways. The outcome from this study will potentially provide a sensitive and robust method for the early detection of glaucoma.

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