Current Search: Retinal Degeneration (x)
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- Title
- PHOTORECEPTOR DEGENERATION AND ABNORMAL RETINAL VASCULOGENESIS.
- Creator
- Nguyen, Matthew, Shen, Wen, Florida Atlantic University, Department of Biomedical Science, Charles E. Schmidt College of Medicine
- Abstract/Description
-
Abnormal vasculature in the retina, specifically tortuous blood vessels, are common to many of the most prevalent retinal degenerative diseases currently affecting millions across the world. The mechanisms of their formation and development in the context of retinal degenerative disease, however, are still poorly understood. The rd1 and rd10 mice are relatively well-studied animal models of retinal degenerative disease, however, there lacks a systematic characterization of vascular changes co...
Show moreAbnormal vasculature in the retina, specifically tortuous blood vessels, are common to many of the most prevalent retinal degenerative diseases currently affecting millions across the world. The mechanisms of their formation and development in the context of retinal degenerative disease, however, are still poorly understood. The rd1 and rd10 mice are relatively well-studied animal models of retinal degenerative disease, however, there lacks a systematic characterization of vascular changes co-related to photoreceptor degeneration in the rd1 and rd10 retina. Here, we utilize advancements in confocal microscopy, immunohistochemistry, and image analysis software in order to systematically characterize vascular changes before and after retinal development in the rd1 and rd10 mice. We show that there are plexus specific changes in the retinal vasculature that parallel photoreceptor degeneration. Such information will be of particular use to future studies investigating the role of vascular changes in retinal degenerative disease therapies.
Show less - Date Issued
- 2021
- PURL
- http://purl.flvc.org/fau/fd/FA00013818
- Subject Headings
- Retinal Degeneration, Retinal Vessels--pathology, Retina—Diseases, Photoreceptors
- Format
- Document (PDF)
- Title
- Hypoxia-regulated gene therapy for the treatment of subretinal neovascularization in age-related macular degeneration.
- Creator
- Smith, George Wesley Tyler., Charles E. Schmidt College of Science, Center for Complex Systems and Brain Sciences
- Abstract/Description
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Age-related macular degeneration (AMD) is the leading cause of blindness in the western world for people over 60 years of age. The most severe pathological event of AMD is choroidal neovascularization (CNV), the process of new vessel formation emerging from the choroid. The new vessels extend into the normally avascular photoreceptor cell layer, where they leak fluid and cause photoreceptor cell death. CNV is thought to be initiated by hypoxia and chronic inflammation, which occur due to...
Show moreAge-related macular degeneration (AMD) is the leading cause of blindness in the western world for people over 60 years of age. The most severe pathological event of AMD is choroidal neovascularization (CNV), the process of new vessel formation emerging from the choroid. The new vessels extend into the normally avascular photoreceptor cell layer, where they leak fluid and cause photoreceptor cell death. CNV is thought to be initiated by hypoxia and chronic inflammation, which occur due to abnormal, age-related changes within the retinal pigmented epithelium (RPE). These events cause increased expression of the angiogenic protein vascular endothelial growth factor (VEGF) via hypoxiainducible factor-1 (HIF-1), a transcription factor that is vital in regulation of cellular responses to hypoxic and inflammatory conditions. Increased VEGF signaling stimulates proliferation and migration of vascular endothelial cells and facilitates the neovascular process. To target the early pathological events that lead to CNV, we have engineered a novel gene therapy vector that uses HIF-1 regulation to stimulate production of an angiostatic protein, endostatin from the RPE. The purpose of this study was to characterize the activity of our hypoxiaregulated, RPE-specific promoter in vitro, and investigate the effects of regulated endostatin expression, driven by our regulated promoter, on CNV in a mousemodel. We found the regulated promoter construct has robust activity in vitro only in RPE cells, and is conditionally responsive in hypoxic conditions., In the laserinduced CNV model, CNV area was 80% smaller (P<0.0001) in eyes treated with the hypoxia-regulated, RPE-specific endostatin vector than in untreated eyes. CNV area was equally reduced in eyes treated with an unregulated endostatin vector (CMV-endostatin). However, less endostatin protein was detected in eyes treated with the regulated vector. Since it is unknown whether broad and constitutive endostatin expression will have damaging effects within the retina, it may be safer to limit its expression to pathological conditions. We have demonstrated that local, hypoxia-regulated expression of endostatin can effectively inhibit CNV, and thus, offers the further possibility of a prophylactic treatment for neovascular AMD.
Show less - Date Issued
- 2010
- PURL
- http://purl.flvc.org/FAU/2979379
- Subject Headings
- Retinal degeneration, Treatment, Eye, Aging, Neovascularization inhibitors
- Format
- Document (PDF)
- Title
- Engineered and natural TIMP mutations.
- Creator
- Hamze, Asmaa Bilal., Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
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Tissue inhibitors of metalloproteinases (TIMPs) comprise a family of four proteins in humans that modulate the turnover of the extracellular matrix by regulating the activities of endopeptidases that catalyze its degradation, especially the matrix metalloproteinases (MMP). In general, the four TIMPs are broad-spectrum tight binding inhibitors of MMPs with individual differences in specificity. In this study, we attempted to understand the basis of such variation by using membrane type-1 MMP ...
Show moreTissue inhibitors of metalloproteinases (TIMPs) comprise a family of four proteins in humans that modulate the turnover of the extracellular matrix by regulating the activities of endopeptidases that catalyze its degradation, especially the matrix metalloproteinases (MMP). In general, the four TIMPs are broad-spectrum tight binding inhibitors of MMPs with individual differences in specificity. In this study, we attempted to understand the basis of such variation by using membrane type-1 MMP (MT1-MMP) as a model, since it is inefficiently inhibited by TIMP-1 in contrast with the other TIMPs. We designed and engineered mutations in the N-domain of TIMP-1, based on current knowledge of TIMP interactions. By measuring inhibition levels of each mutant against several MMPs, including MT1-MMP, we were able to obtain a triple mutant with an vii improved affinity for MT1-MMP., Our results, along with previous data, confirm that multiple residues in the critical interface segments between TIMPs and MMPs, namely at positions 2, 4, 5, 6, and 98, are key in determining the basic interaction between the two molecules. The second part of this work focused on naturally occurring mutations in TIMP-3 which cause an early form of macular degeneration called Sorsby's Fundus Dystrophy (SFD). The TIMP-3 mutants identified so far share certain features but the mechanism by which they result in macular disease is not yet understood. As an initial step, we expressed recombinant TIMP-3 carrying a truncation mutation, glutamic acid 139 to a stop codon (E139X), and assessed its activity towards representative MMPs and tumor necrosis factor-(Sa (Bconverting enzyme, another metalloproteinase normally inhibited by TIMP-3. Our results indicate that this mutation does not impair the inhibitory activity of TIMP-3., Expression of this mutant in mammalian retinal cells revealed a difference in localization between wild-type and E139X mutant TIMP-3. Therefore, we concluded that the SFD mutations may actually influence the processing and/or binding properties of TIMP-3 in the retina.
Show less - Date Issued
- 2008
- PURL
- http://purl.flvc.org/FAU/186296
- Subject Headings
- Proteolytic enzymes, Extracellular matrix proteins, Metalloproteinases, Inhibitors, Apoptosis, Retinal degeneration, Research
- Format
- Document (PDF)
- Title
- Integrin αVβ5-mediated Removal Of Apoptotic Cell Debris By The Eye Lens And Its Inhibition By UV-light Exposure.
- Creator
- Bakina, Olga, Kantorow, Marc, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biomedical Science
- Abstract/Description
-
The lens is a crystallin tissue of the anterior part of the eye that focuses light onto the retina. Aged-related cataract, which is the result of loss of lens transparency, is the most common cause of blindness in the world. Being constantly exposed to UV-light, lens is significantly affected by its UVA spectrum. UV-light exposure has been shown to result in apoptosis of lens cells which can lead to cataract formation. This suggests the need for molecular mechanisms to remove apoptotic debris...
Show moreThe lens is a crystallin tissue of the anterior part of the eye that focuses light onto the retina. Aged-related cataract, which is the result of loss of lens transparency, is the most common cause of blindness in the world. Being constantly exposed to UV-light, lens is significantly affected by its UVA spectrum. UV-light exposure has been shown to result in apoptosis of lens cells which can lead to cataract formation. This suggests the need for molecular mechanisms to remove apoptotic debris from the lens. In the set of experiments it was proven that integrin αvβ5-mediated pathway is involved in phagocytosis of apoptotic cell debris in the ocular lens, thus contributing to its homeostasis. Additionally, it was shown that exposure to UV-light plays role in cataract formation by influencing integrin αvβ5-mediated phagocytosis function.
Show less - Date Issued
- 2016
- PURL
- http://purl.flvc.org/fau/fd/FA00004568
- Subject Headings
- Eye x Diseases--Research., Retinal degeneration., Cellular control mechanisms., Apoptosis
- Format
- Document (PDF)
- Title
- Hypoxia-regulated glial cell-specific gene therapy to treat retinal neovascularization.
- Creator
- Biswal, Manas Ranjan., Charles E. Schmidt College of Science, Center for Complex Systems and Brain Sciences
- Abstract/Description
-
Diabetic retinopathy is an ischemic retinal neovascular disease causing vision loss among adults. The studies presented involve the design and testing of a gene therapy vector to inhibit retinal revascularization, similar to that found in diabetic retinopathy. Gene therapy has proven to be an effective method to introduce therapeutic proteins to treat retinal diseases. Targeting a specific cell type and expression of therapeutic proteins according to the tissue microenvironment should have an...
Show moreDiabetic retinopathy is an ischemic retinal neovascular disease causing vision loss among adults. The studies presented involve the design and testing of a gene therapy vector to inhibit retinal revascularization, similar to that found in diabetic retinopathy. Gene therapy has proven to be an effective method to introduce therapeutic proteins to treat retinal diseases. Targeting a specific cell type and expression of therapeutic proteins according to the tissue microenvironment should have an advantage over traditional gene therapy by avoiding unwanted transgene expression. Hypoxia plays a significant role in the pathophysiology of many retinal ischemic diseases. Retinal Mèuller cells provide structural and functional support to retinal neurons, as well as playing a significant role in retinal neovascularization. Targeting Mèuller cells may be an effective strategy to prevent retinal neovascularization under pathological conditions. ... The hypoxia regulated, glial specific vector successfully reduced the abnormal neovascularization in the periphery by 93% and reduced the central vasobliterated area by 90%. A substantial amount of exogenous endostatin was produced in the retinas of P17 OIR mice. A significant increase in human endostatin protein and reduced vascular endothelial growth factor (VEGF) were identified by Western blot and ELISA, respectively. These findings suggest hypoxia-regulated, glial cell-specific scAAV mediated gene expression may be useful to prevent blindness found in devastating retinal diseases involving neovascularization.
Show less - Date Issued
- 2012
- PURL
- http://purl.flvc.org/FAU/3359290
- Subject Headings
- Diabetic retinopathy, Research, Methodology, Gene therapy, Retinal degeneration, Treatment, Neovascularization inhibitors, Mitochondrial pathology, Retina, Cytology, Gene mapping
- Format
- Document (PDF)