Two broad areas of investigation are underway in the Department of Ophthalmic Research in the Cole Eye Institute. One is focused on neurodegenerative diseases of the retina with the overall goal of understanding the basic mechanisms underlying early and late onset forms of inherited retinal diseases including retinitis pigmentosa, juvenile and age-related forms of macular degeneration, and glaucoma. The second area of investigation is on the cornea, with a focus on understanding the fundamental control of wound healing and corneal clarity; and of immune privilege underlying graft rejection and inflammation.
Research in the laboratory of Joe G. Hollyfield, Ph.D., seeks to define the organization of the matrix surrounding the extensions of photoreceptor cells projecting from the outer surface of the retina. Novel molecules present in this matrix are targets for involvement in degenerative retinal diseases, including age related macular degeneration (AMD). Ongoing studies are defining how two novel proteins present in this matrix (SPACR and SPACRCAN) interact to form a stable matrix and the involvement of hyaluronan as the scaffold on which this matrix is organized. His laboratory is also involved in the characterization of sub-types and composition of drusen, debris that accumulates below the retinal pigment epithelium and is the major risk factor for developing AMD.
Research in the laboratory of John W. Crabb, Ph.D., seeks a better understanding of the biochemistry of vision in AMD and the visual cycle. Ongoing proteomic studies seek the identity of proteins, oxidative modifications and plasma biomarkers associated with the pathogenesis of AMD. A long-term goal is the development of a blood test for AMD susceptibility that will allow identification of those at risk for AMD prior to clinical evidence of the disease. Other proteomic studies are focused upon identifying protein-protein interactions in the retinal pigment epithelium associated with the rod visual cycle regeneration of 11-cis-retinoid.
Human genetics studies are underway in the laboratory of Stephanie A. Hagstrom, Ph.D., involving a candidate gene approach using DNA samples from patients with inherited retinal diseases, the selection of candidate genes and large-scale mutation screening of the DNA samples using molecular genetic techniques. Following the identification of a disease-causing gene, the goal is to define the molecular mechanism responsible for retinal degeneration. One of the genes identified (named TULP1) causes a form of autosomal recessive retinitis pigmentosa. Functional studies underway on the gene product suggest that it is involved in the polarized transport of proteins from their site of synthesis in the inner segment of the photoreceptor cell to their final destination.
Studies in the laboratory of Neal S. Peachey, Ph.D., focus on electrophysiological studies of the retina, within two general research areas. The first uses retinal electrophysiology to define the functional status of the retina. Stimulation and recording protocols that allow the electrical activity of specific retinal cell types to be studied are applied to animal models and to patients with retinal disorders. The second research area seeks to better understand the cellular origins of the electrophysiological signals that are recorded. These studies involve animal models with well-defined gene defects as well as pharmacological manipulation of retinal synaptic transmission.
Following photoreceptor degeneration inner retinal synaptic organization becomes dynamic. As a first step in controlling these reactive events, research in the laboratory of Sherry L. Ball, Ph.D., is defining how these dynamic events alter retinal circuitry. First we are identifying inner retinal circuits in the healthy retina. Second, we are assessing function and structure in each pathway during photoreceptor degenerative diseases. These measures will serve as a basis for exploring and evaluating treatment strategies to slow degenerative events and thus vision loss.
Studies in the laboratory of Sanjoy Bhattacharya, Ph.D., focus on retinal ganglion cell loss caused by glaucoma, a group of progressive irreversible blinding disorders. Primary open angle glaucoma is often associated with elevated intraocular pressure; the latter is attributed to resistance to aqueous outflow in the anterior eye segment. All glaucomas are characterized by slowly progressing damage to the optic nerve leading to blindness. Using a proteomic approach, several proteins (i.e., cochlin and peptidyl arginine deiminase type II) have been identified in glaucomatous tissues and are currently being evaluated for their causal involvement in the disease process using animal and tissue culture models.
A subset of patients with AMD have an acute vascular hemorrhage caused by abnormal blood vessel growth (neovascularization) at this interface. The laboratory of Bela Anand-Apte, M.D., Ph.D. is defining the basic mechanisms involved in physiological and pathological neovascularization processes, with a final goal of designing therapeutic approaches to combat neovascularization in disease states.
Abnormal blood vessel development is also involved in diabetic retinopathy. The focus of studies in the laboratory of Preenie Senanayake, Ph.D., is on the role of angiotensin II in the development and maintenance of proliferative diabetic retinopathy. To define the underlying mechanisms the molecular and cellular consequences of genetic and physiological perturbations of the angiotensin system are under analysis in diabetic rat models and in cell culture.
Triamcinolone acetonide (TA) is a glucocorticoid that is rapidly becoming a primary treatment for eye disease associated with permeability and proliferation of blood vessels. Intravitreal TA is reported to reduce visual loss from subfoveal diabetic macular edema and is used as combination therapy with ocular photodynamic therapy for exudative age-related macular degeneration. The preliminary success of these results in humans suggests that TA may be an exciting new treatment for premature infants at high risk from sight-threatening retinal detachment due the effects of blood vessel permeability and proliferation associated with retinopathy of prematurity (ROP). Studies underway in the laboratory of Jonathan E. Sears, M.D., are directed at defining the mechanism by which glucocorticoids inhibit pathologic angiogenesis and vasopermeability. The long-term aim of this work is to develop steroid-like agents for treating ROP in the absence of common, deleterious steroid side effects.
Studies on the lysosomal system in the retinal pigment epithelium are conducted in the laboratory of George Hoppe, Ph.D. The impact of oxidative damage on cellular phagolysosomal function is of primary interest and the effects of oxidative stress on lysosomal activity constitutes a phenomenon of general pathobiology, which is particularly exaggerated in retina. The retinal pigment epithelium was chosen for analysis because its phagolysosomal apparatus is directly linked to the renewal and survival of photoreceptors. Nonetheless, from the mechanistic standpoint, the status of the phagolysosomal pathway is perhaps equally important for antigen presentation by dendritic cells, degradation of amyloid plaques by neuroglia in Alzheimer’s disease, and formation of Lewy bodies in neurons of Parkinson patients. Lipofuscin-like autofluorescent pigment is also routinely found within macrophages in atherosclerotic lesions. Accordingly, results from this analysis have broad application.
Studies conducted by Steven E. Wilson, M.D., involve cell communication in the cornea. Specifically, the stromal-epithelial interactions involved in corneal wound healing, including keratocyte apoptosis, keratocyte proliferation, bone marrow cell involvement in corneal wound healing, and myofibroblast generation associated with complications of corneal surgery underlying stromal opacity, inadequate predictability of correction, and neurotrophic epitheliopathy.
The program of Victor L. Perez, M.D., is developing in vivo models of ocular inflammation to study the mechanisms of immuno-regulation and develop novel immunotherapeutic treatment of these disorders. One of the research projects is dedicated to investigate in vivo immune responses after orthotopic corneal allograft transplantation in a murine model of high-risk corneal transplantation. Specifically, the focus is in understanding how early innate immune responses mediated by neutrophils, chemokines and macrophages regulate adaptive T-cell responses to alloantigen. An in vivo animal model has been developed in which immunological responses during corneal transplantation can be monitored in real time with time-lapsed image analysis that provides unique information about the immunobiology of graft rejection and complements the immunology experiments.
Studies in the laboratory of Rajiv R. Mohan, Ph.D., focus on defining selective gene transfer approaches for the cornea and studying corneal wound healing. Selective expression of therapeutic genes at the desired location and duration in the cornea may offer novel and potentially more effective treatment for corneal haze, neovascularization and other prevalent corneal diseases/disorders with minimal side effects. His laboratory is also exploring whether site-selective tissue targeted gene transfer approaches can be applied for (a) identifying preventative or interventional strategies for different corneal diseases/disorders, (b) studying the specific function and role of disease-causing genes such as TGFβ and BIGH3 in corneal pathology in vivo, and (c) developing experimental animal models for studying genetic corneal dystrophies.
More information can be found at www.clevelandclinic.org/eye/research/
Lerner Research Institute
Cleveland Clinic, Mail Code NB21
9500 Euclid Avenue
Cleveland, Ohio 44195
