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The Ohio State University Department of Ophthalmology
Continuing Projects: Corneal Biomechanical and Hydration Model before and after Refractive Surgery. (Grzybowski and Roberts) A combination of topography, wavefront, reflectivity, and autorefraction data will be used to create a model of corneal biomechanical response to refractive surgery that includes the critical factor of corneal hydration. Clinical measurements on 7 LASIK and 11 normal subjects have been obtained. Subjects who have undergone LASIK surgery demonstrate an exaggerated swelling response to induced corneal edema. Using the Heidelberg OCT reflectance a correlation between percent swelling and percent change in reflectance for post-LASIK corneas in the peripheral region may be related to the lack of tension in the peripheral lamellar segments as a result of the surgical procedure, which results in a decreased scatter with increased swelling. A manuscript is in review; multiple other manuscripts are in preparation.
CSF Outflow through human Arachnoid Membrane/Optic Nerve Sheath (Grzybowski) The most commonly accepted working mechanism for idiopathic PTC is an increased resistance to outflow of cerebrospinal fluid across the arachnoid membrane. In order to understand this altered resistance and find a pharmaceutical target that can be used in treatment by increasing outflow, ex vivo and in vitro models of CSF outflow through the human arachnoid membrane has been developed. Continued work on the mechanism of fluid transport and mediators that affect it is being undertaken including a study of aquaporins and also a study to block active transport pathways.
The Influence of Ocular Pulse Amplitude in Glaucoma (Roberts) Work will continue on the hypothesis proposed previously, describing the influence of the variation in intraocular pressure caused by the heart beat (ocular pulse amplitude or OPA) on the development and progression of glaucoma. Basic modeling studies have been completed, and a manuscript is being prepared for submission to Investigative Ophthalmology and Visual Science. We presented a study at ARVO comparing changes in IOP and OPA in the sitting, supine, and Trendelenburg positions and showed that as IOP increased from sitting to supine, OPA also increased. However, in the change of position from supine to Trendelenburg, IOP was stable but OPA decreased, demonstrating a reduction in ocular blood flow. A Visiting Scholar has been recruited for the summer to investigate this further by gathering data in the operating room from patients undergoing surgery. During surgery, there will be a natural variation in systemic blood pressure and heart rate. Arterial, venous, and ocular pressure waveforms will be recorded simultaneously, and signal analysis will be performed to investigate the determinants of the ocular pulse waveform.
Corneal Biomechanical Properties in Keratoconus (Roberts) Work will continue on the new hypothesis proposed for biomechanical progression in Keratoconus, in which a confined corneal region has a reduction in elastic modulus. This confined region bulges due to a specific relationship between deformation and applied force. As the bulging occurs, the cornea becomes thinner. This serves as a stress concentration and drives further deformation. An NIH grant application was prepared in collaboration with an investigator from the Cleveland Clinic Foundation, William J. Dupps, MD, PhD. We have received additional comments from reviewers, which has guided the additional collection of data in support of this hypothesis and we plan to resubmit the proposal for a final time in the coming year.
Intravitreal anti-VEGF agents such as avastin, lucentis and macugen with wet macular degeneration. (John Christoforidis, M.D.) Currently, intravitreal injections of anti-VEGF agents, particularly bevacizumab (avastin) and ranibizumab (lucentis) are by far the most commonly performed procedures in the field of retina today. However, we can only assume that these injected substances are confined within the ocular contents and do not extend into the systemic circulation or through the CNS via the optic nerve. This is especially possible in the conditions that are treated with anti-VEGF agents since there is a breakdown of the blood-brain/retinal barrier due to choroidal neovascularization in the wet form of macular degeneration and other similar conditions. Because of the low levels of endogenous VEGF in the serum (100-200 pg/ml), any escape of VEGF from the vitreous cavity into the systemic circulation or CNS may significantly suppress systemic VEGF levels. Known adverse effects of systemic avastin include epistaxis, CNS hemorrhages and delayed wound healing. Previous work recently conducted in my lab has demonstrated that intravitreal agents suppress the formation of neovascularization in the proliferative phase of wound healing.
To date, we are the only center that has been able to image these radiolabelled substances in vivo. In conjunction with the Department of Radiology, we have established a methodology for radiolabelling these agents and have gathered preliminary data using this PET/CT in normal dutch-belted rabbit eyes. This has demonstrated that these labeled agents are indeed confined within the globe of the eye. However, in clinical practice the patients that undergo these procedures have undergone breakdown of the blood-brain barrier at the retinal-choroidal interface. Our project would have much greater clinical significance if this procedure could be performed on an animal model with choroidal neovascularization. This is typically created with the use of laser photocoagulation and confirmed with fluorescein angiography.
___ OSU Department of OphthalmologyDr. Abdel-Rahman
W.R. Bryan Diabetic Eye Disease Grant Program: New ProposalIdentification of Novel Agents from Medicinal Herbal Extracts for Treatment of Eye Diseases Associated with Neo-Vascularization INTRODUCTIONDiabetic retinopathy is the leading cause of visual loss for Americans under the age of 65. Sixteen million individuals in the USA are diabetic and 40,000 new patients per year suffer from ocular complications of the disease, often a result of retinal edema or neo-vascularization (invasive new vessel formation). Worldwide, 194 million individuals have diabetes and this number is expected to more than double between now and 2030 (1). Diabetic retinopathy is observed in 40% of individuals with diabetes and over 8% of diabetic patients have vision loss from microvascular complications(2). There is considerable evidence that Vascular Endothelial Growth Factor (VEGF) is a prime regulator of angiogenesis (the process of new vessel formation)(3). However, the process is complex with interaction of multiple other angiogenic molecules(4). Advances in the understanding of the angiogenic processes have led to the development of several compounds that are currently approved for the treatment of angiogenic diseases of the eye(4). These commercially available drugs (pegaptanib, ranibizumab, and bevacizumab), all inhibitors of VEGF, are used widely via intra-vitreal injection for the treatment of many eye diseases associated with neo-vascularization such as diabetic retinopathy, age related macular degeneration (AMD), diabetic macular edema, macular edema secondary to retinal vein occlusion in addition to several other neo-vascular eye diseases. Significant challenges remain in finding the appropriate angiostatic with high safety profile, economically affordable, and easily administered for the treatment of neo-vascular eye diseases. Also, identifying agents that work not only through inhibition of VEGF but also on the other angiogenic molecules can improve the outcomes of many of the patients with neo-vascular eye diseases(5). SPECIFIC AIMThe aim of this project is to identify novel anti-angiogenic agents from medicinal plants and herbs for treatment of eye diseases associated with neo-vascularization such as diabetic retinopathy and age related macular degeneration. The concept is that medicinal herbs, especially the ones that have been utilized for many years, will be less toxic with fewer side effects and cheaper than the currently available treatments for diabetic retinopathy. IMPACT OF SUCCESFUL OUTCOMECurrent strategy for management of diabetic retinopathy is to treat the patients once the condition is diagnosed. Even with optimum control of diabetes numerous patients develops diabetic retinopathy. Current pharmaceutical treatments for the control of neo-vascularization mostly depend on the inhibition of VEGF. Such therapies are rather invasive requiring frequent intra-ocular injection of the therapeutic agents. These therapies are also extremely expensive. Due to the complexity of the angiogenic process, single agent therapy is inefficient in some patients. Medicinal herbs especially the ones that have been utilized for many years are less toxic with fewer side effects and cheaper than the currently available treatments for diabetic retinopathy. Identification of therapeutic active extracts, which can be used in conjunction with the current treatments or separately, will improve the outcome of patients with diabetic retinopathy. In addition, these extracts can be used for prevention of the development of new vessels in individuals with high risk for development of diabetic retinopathy. ____ W.R. Bryan Diabetic Eye Disease Grant Program: New ProposalDIABETIC RETINOPATHY – Breaking the Code on Capillary Crosstalk: The Key to Diabetic Blindness, Stroke and Death (Lubow) HypothesisBlinding blood vessel complications of diabetes mellitus [DM] originate with specific cellular responses to their environment. The cellular environment is determined by serum factors modified by glucose levels, which are abnormal in DM. The cells involved are those that make up the microvasculature; these are the capillary endothelial cell and the associated pericyte. Because pericyte density is greatest in the retina it is the retinal capillaries that provide us with the earliest signs of diabetic microvascular disease. Study of retinal capillary cell structures and molecular signals offers insight into why and how things go wrong in DM, first at the cellular level, but eventually at the capillary, large vessel and the tissue level. The signaling messages to – and between - these retinal capillary endothelial cells and pericytes and are identifiable. They can be recognized and modified, and used to save vision and life. This work can be done in laboratory cell cultures, and in diabetic mice. We have the facilities to develop and to work with both the cultures and the diabetic mice here in our own research group, and with our collaborators at OSUMC. Specific Aims1] Establish, expand and maintain cell cultures of retinal capillary endothelial cells. 2] Establish, expand and maintain cell cultures of retinal capillary pericytes. 3] Establish and maintain cell media to provide homeostasis equivalent to normal and to DM cellular environments that will serve as a platform for further work on the microvascular pathology of DM
Progress Report on Continuing Projects
The Effect of Diabetes on Biomechanical Properties of the Eye (Roberts)I. Objective: Our objective is to quantify the effect of diabetes on the biomechanical properties of the eye by investigating the effect of stiffening of eye structures in diabetes secondary to non-enzymatic collagen glycosylation on intraocular eye pressure measurements and evaluate the effect diabetes has on the biomechanical properties of the eye in vivo. II. Background and rationale: Diabetes mellitus (DM) has been found to have a protective effect against progression of ocular hypertension to primary open angle glaucoma1. The Ocular Hypertensive Treatment Study (OHTS) group showed that diabetes mellitus (DM) was a protective factor against the progression of ocular hypertension (OHT) to primary open angle glaucoma (POAG). It is also well known that DM causes covalent cross-linking induced by glycosylation, which has been shown to increase the tensile strength of diabetic skin, tendons2, and lamina cribrosa of rats3. We will investigate the possibility that the protective effect is secondary to the biomechanical changes of stiffening of eye structures secondary to non-enzymatic collagen glycosylation. III. Methods: 50 patients with diabetes mellitus (DM) without associated retinopathy and 50 patients with DM with associated retinopathy will be recruited from the ophthalmology clinic. To ensure the effects are secondary to diabetes alone patients with previous eye trauma, invasive eye surgery, corneal edema or corneal disease will be excluded. 100 patients from the ongoing study of the normal aging population from protocol number 2006H0094 will be age, sex, and race-matched and recorded as controls. The patients age, race, how many years they have had diabetes and their blood glucose control will be recorded as reported by the patient. Tonometry will be measured with Goldmann applanation tonometry (GAT), and Pascal dynamic contour tonometry (DCT). DCT will also be used to measure ocular pulse amplitude (OPA). Blood pressure will be measured due to its correlation and effect on OPA. Pachymetry will be preformed using a hand held pachymeter. Ocular hysteresis and corneal resistance factor (CRF) will be recorded with the Reichert ocular response analyzer (ORA). The diabetic patients most recent hemoglobin A1c will also be recorded. Statistical analysis will be conducted using a student-t test to compare the 2 groups. Further analysis will be conducted to see if there is a correlation between length of disease or most recent hemoglobin A1c and the various ocular rigidity parameters. All significance values have been set a priori at p<0.05. All measurements that will be preformed in this study are well-accepted, non-invasive procedures that are routinely used in the ophthalmology clinic. IV. Status of the Research The Institutional Review Board Protocol was written, submitted, and ultimately approved. Subjects were recruited and data acquired by medical student, Srinivas Kondapalli. The work was presented at ARVO 2010.4 References: 1. Brandt JD, et al. Central Corneal Thickness in the Ocular Hypertension Treatment Study. Ophthalmology. 2001 Oct;108(10):1779-88 2. Reiser KM. Nonenzymatic glycation of collagen in aging and diabetes. Proc Soc Exp Biol Med 1991; 196:17–26 3. Spoerl E, et al. Biomechanical properties of lamina cribrosa and peripapillary sclera in diabetic rats. Poster presentation at ARVO. May 1, 2006; poster 1226/B162. 4. Kondapalli SA, Roberts CJ, Mahmoud A, Weber PA, Peterson J. The Effect of Diabetes on Biomechanical Properties of the Cornea. ARVO 2010: 4631.
Correlation of Histological Retinal Microvascular Perfusion Defects with Histological Subendocardial and Renal Perfusion Defects in Diabetes (Grzybowski)
Study Relevance Retinal capillary perfusion is well demonstrated with fluorescein retinal angiography. Cardiac capillary perfusion is poorly recognized, but manifested by subendocardial hypoperfusion. Renal capillary disease is recognized histopathologically by needle biopsy, but otherwise not easily demonstrable. These three critical areas are believed to be involved by the vascular disease of diabetes mellitus, as well as in lupus, hypertension, and other vasculopathies. In the future, we plan to show the relevance of accurately visualized retinal perfusion abnormalities via fluorescein neuroretinal angiography. Additional capillary perfusion defects, in those cases where such information will be available, will be shown by cardiac magnetic resonance imaging (CMR) and by appropriate clinical evaluation of renal function. We also predict that a subset of DM patients has abnormal retinal angiography, but normal MPRI and renal evaluation, who can be identified for subsequent longitudinal studies to assess the predictive value of retinal angiography for myocardial and renal disease. For this first phase of the project, we plan to show a correlation in retinal microvascular perfusion defects with subendocardial and renal perfusion defects using histology and image processing in normal and diabetic autopsy tissues. Hypothesis We hypothesize that retinal capillary perfusion abnormalities in diabetes mellitus (DM) will predict equivalent vascular disease manifested by diffuse subendocardial ischemia (in contradistinction to the epicardial ischemia of coronary artery disease) and by renal impairment with vasculopathies involving capillary perfusion and manifested initially by microalbuminuria. ________________________ |
W. R. Bryan Diabetic Eye Disease Research Fund 2008 OLERF Annual Report (PDF file) |
