Connecting the pathways of retinal ganglion cell survival and death in glaucoma: new tools to diagnose, repair and regenerate
<p>A recent analysis of blindness and vision impairment trends over the past 30 years by the Vision Loss Expert Group for the Global Burden of Disease Study revealed that glaucoma remains the leading cause of irreversible blindness worldwide in an ageing population. The mechanisms underlying r...
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| Format: | Thesis |
| Language: | English |
| Published: |
2021
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| _version_ | 1826315502898642944 |
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| author | Khatib, TZ |
| author2 | Martin, K |
| author_facet | Martin, K Khatib, TZ |
| author_sort | Khatib, TZ |
| collection | OXFORD |
| description | <p>A recent analysis of blindness and vision impairment trends over the past 30 years by the Vision Loss Expert Group for the Global Burden of Disease Study revealed that glaucoma remains the leading cause of irreversible blindness worldwide in an ageing population. The mechanisms underlying retinal ganglion cell degeneration in glaucoma are not fully understood. </p>
<p>This thesis examines two key features of glaucomatous neurodegeneration, namely impairment of optic nerve axonal transport and dysregulation of aqueous outflow. </p>
<p>First we demonstrate the continued need to develop new diagnostic and therapeutic approaches for glaucoma by assessing rates of glaucoma progression in the local Cambridge population. We show there is still a clear rate of progression despite tertiary level access to the best treatments currently available.</p>
<p>We describe a new non-invasive tool to assess and quantify the dysregulation of aqueous outflow. Despite being a key therapeutic target in current clinical practice, our understanding of this system is derived largely from post-mortem studies, indirect estimates or, more recently, invasive techniques that alter the physiology of aqueous outflow and are limited in the information they provide. There are currently no non-invasive techniques available that directly visualise detailed aqueous outflow in vivo. We use a non-invasive imaging modality developed to image the anterior microcirculation of the human eye – haemoglobin video imaging – to examine aqueous outflow into the episcleral venous circulation in detail, and to observe and quantify alterations in aqueous outflow following treatments that aim to selectively target this pathway.</p>
<p>We then evaluate a combined receptor-ligand gene therapy
onstruct which overexpresses brain derived neurotrophic factor and its receptor tropomyosin kinase B on optic nerve axonal transport and retinal ganglion cell function. We use a rat glaucoma model and a humanised tauopathy model of reduced axonal transport and showed combined overexpression is more effective in stimulating axonal transport than either receptor administration or ligand administration alone. We also demonstrate functional recovery in the glaucoma model.</p>
<p>Furthermore, we offer promising evidence there may be an improvement in short term memory loss in the tauopathy model, suggesting that this strategy to target intrinsic mechanisms to improve neuronal function and facilitate repair may be relevant to multiple neurodegenerative diseases.</p>
<p>We then assess whether manipulating the degenerative process could also be associated with optic nerve regeneration in experimental glaucoma. We demonstrate for the first time the glaucomatous optic nerve also has the potential to regenerate using strategies previously only used after traumatic injury.</p> |
| first_indexed | 2024-03-07T06:24:41Z |
| format | Thesis |
| id | oxford-uuid:f3dcbb08-4bd1-4c2f-890a-2b362fce14da |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:26:54Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | oxford-uuid:f3dcbb08-4bd1-4c2f-890a-2b362fce14da2024-11-29T08:16:29ZConnecting the pathways of retinal ganglion cell survival and death in glaucoma: new tools to diagnose, repair and regenerateThesishttp://purl.org/coar/resource_type/c_db06uuid:f3dcbb08-4bd1-4c2f-890a-2b362fce14daNervous system--RegenerationOptic nerveGlaucomaImaging systems in medicineGene therapyAxonsEnglishHyrax Deposit2021Khatib, TZMartin, KOsborne, N<p>A recent analysis of blindness and vision impairment trends over the past 30 years by the Vision Loss Expert Group for the Global Burden of Disease Study revealed that glaucoma remains the leading cause of irreversible blindness worldwide in an ageing population. The mechanisms underlying retinal ganglion cell degeneration in glaucoma are not fully understood. </p> <p>This thesis examines two key features of glaucomatous neurodegeneration, namely impairment of optic nerve axonal transport and dysregulation of aqueous outflow. </p> <p>First we demonstrate the continued need to develop new diagnostic and therapeutic approaches for glaucoma by assessing rates of glaucoma progression in the local Cambridge population. We show there is still a clear rate of progression despite tertiary level access to the best treatments currently available.</p> <p>We describe a new non-invasive tool to assess and quantify the dysregulation of aqueous outflow. Despite being a key therapeutic target in current clinical practice, our understanding of this system is derived largely from post-mortem studies, indirect estimates or, more recently, invasive techniques that alter the physiology of aqueous outflow and are limited in the information they provide. There are currently no non-invasive techniques available that directly visualise detailed aqueous outflow in vivo. We use a non-invasive imaging modality developed to image the anterior microcirculation of the human eye – haemoglobin video imaging – to examine aqueous outflow into the episcleral venous circulation in detail, and to observe and quantify alterations in aqueous outflow following treatments that aim to selectively target this pathway.</p> <p>We then evaluate a combined receptor-ligand gene therapy onstruct which overexpresses brain derived neurotrophic factor and its receptor tropomyosin kinase B on optic nerve axonal transport and retinal ganglion cell function. We use a rat glaucoma model and a humanised tauopathy model of reduced axonal transport and showed combined overexpression is more effective in stimulating axonal transport than either receptor administration or ligand administration alone. We also demonstrate functional recovery in the glaucoma model.</p> <p>Furthermore, we offer promising evidence there may be an improvement in short term memory loss in the tauopathy model, suggesting that this strategy to target intrinsic mechanisms to improve neuronal function and facilitate repair may be relevant to multiple neurodegenerative diseases.</p> <p>We then assess whether manipulating the degenerative process could also be associated with optic nerve regeneration in experimental glaucoma. We demonstrate for the first time the glaucomatous optic nerve also has the potential to regenerate using strategies previously only used after traumatic injury.</p> |
| spellingShingle | Nervous system--Regeneration Optic nerve Glaucoma Imaging systems in medicine Gene therapy Axons Khatib, TZ Connecting the pathways of retinal ganglion cell survival and death in glaucoma: new tools to diagnose, repair and regenerate |
| title | Connecting the pathways of retinal ganglion cell survival and death in glaucoma: new tools to diagnose, repair and regenerate |
| title_full | Connecting the pathways of retinal ganglion cell survival and death in glaucoma: new tools to diagnose, repair and regenerate |
| title_fullStr | Connecting the pathways of retinal ganglion cell survival and death in glaucoma: new tools to diagnose, repair and regenerate |
| title_full_unstemmed | Connecting the pathways of retinal ganglion cell survival and death in glaucoma: new tools to diagnose, repair and regenerate |
| title_short | Connecting the pathways of retinal ganglion cell survival and death in glaucoma: new tools to diagnose, repair and regenerate |
| title_sort | connecting the pathways of retinal ganglion cell survival and death in glaucoma new tools to diagnose repair and regenerate |
| topic | Nervous system--Regeneration Optic nerve Glaucoma Imaging systems in medicine Gene therapy Axons |
| work_keys_str_mv | AT khatibtz connectingthepathwaysofretinalganglioncellsurvivalanddeathinglaucomanewtoolstodiagnoserepairandregenerate |