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postgraduate thesis: Exploration of drug therapy in mouse models of human retinal diseases
Title | Exploration of drug therapy in mouse models of human retinal diseases |
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Authors | |
Issue Date | 2015 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Wang, K. [王可]. (2015). Exploration of drug therapy in mouse models of human retinal diseases. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5689280 |
Abstract | Retinitis pigmentosa (RP) is a series of inherited retinal degenerative diseases mostly caused by the gene mutations in rod photoreceptors, which lead to the primary loss of rod photoreceptors, and the secondary loss of cone photoreceptors. More than 1.5 million people worldwide lose their sight every year as a result of RP disorder.
RP is a hereditary disease with complex causes, there are currently no ideal treatments that are either against primary gene mutations or against the secondary neuronal degeneration. Therapies that aim to preserve photoreceptor function may represent an effective alternative for improving the quality of life of many RP patients.
The main focus of this thesis was to investigate the pathological mechanism of RP and to explore possible therapeutic strategies for it. Although the mechanisms of photoreceptor death remain elusive in RP, multiple mechanisms are suggested to have a role in photoreceptor death. To confirm the involvement of multiple pathways in RP, we systemically applied three multi-target iron-chelator based compounds: VK28, M30, VAR10303and one multi-target traditional Chinese medicine LBP (Lycium barbarum polysaccharides)to the rd10 mouse model of RP. The effectiveness of these drugs was evaluated by morphological, electrophysiological, behavioral and molecular biological analysis. We found thatVK28, M30, VAR10303and LBP appeared to have both short-term and long-term neuroprotective effects on photoreceptor cell. We further identified that these compounds exerted their effects through anti-apoptotic, antioxidant and anti-inflammatory mechanisms. The findings provided more evidence on the involvement of multiple mechanisms in photoreceptor degeneration of RP, suggesting a multi-target drug therapy is more sufficient than a single-targeted manipulation in protecting photoreceptors from degeneration in RP treatment.
Neuroinflammation is suggested to be involved in pathology of glaucoma, but the mechanisms regulating microglia activation are not yet clear. We thus investigated the mechanisms underlying microglia activation in a mouse model of glaucoma. We found that microglia activation played a pathogenic role in AOH-caused retinal ganglion cell (RGC).We also demonstrated that chemokine receptorCX3CR1 in microglia played an important role in regulating microglia activation. Our findings indicate that suppressing neuroinflammation might be a therapeutic option for improving RGC survival in patients with glaucoma. |
Degree | Doctor of Philosophy |
Subject | Retina - Diseases - Animal models Retina - Diseases - Treatment |
Dept/Program | Biomedical Sciences |
Persistent Identifier | http://hdl.handle.net/10722/222370 |
HKU Library Item ID | b5689280 |
DC Field | Value | Language |
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dc.contributor.author | Wang, Ke | - |
dc.contributor.author | 王可 | - |
dc.date.accessioned | 2016-01-13T01:23:16Z | - |
dc.date.available | 2016-01-13T01:23:16Z | - |
dc.date.issued | 2015 | - |
dc.identifier.citation | Wang, K. [王可]. (2015). Exploration of drug therapy in mouse models of human retinal diseases. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5689280 | - |
dc.identifier.uri | http://hdl.handle.net/10722/222370 | - |
dc.description.abstract | Retinitis pigmentosa (RP) is a series of inherited retinal degenerative diseases mostly caused by the gene mutations in rod photoreceptors, which lead to the primary loss of rod photoreceptors, and the secondary loss of cone photoreceptors. More than 1.5 million people worldwide lose their sight every year as a result of RP disorder. RP is a hereditary disease with complex causes, there are currently no ideal treatments that are either against primary gene mutations or against the secondary neuronal degeneration. Therapies that aim to preserve photoreceptor function may represent an effective alternative for improving the quality of life of many RP patients. The main focus of this thesis was to investigate the pathological mechanism of RP and to explore possible therapeutic strategies for it. Although the mechanisms of photoreceptor death remain elusive in RP, multiple mechanisms are suggested to have a role in photoreceptor death. To confirm the involvement of multiple pathways in RP, we systemically applied three multi-target iron-chelator based compounds: VK28, M30, VAR10303and one multi-target traditional Chinese medicine LBP (Lycium barbarum polysaccharides)to the rd10 mouse model of RP. The effectiveness of these drugs was evaluated by morphological, electrophysiological, behavioral and molecular biological analysis. We found thatVK28, M30, VAR10303and LBP appeared to have both short-term and long-term neuroprotective effects on photoreceptor cell. We further identified that these compounds exerted their effects through anti-apoptotic, antioxidant and anti-inflammatory mechanisms. The findings provided more evidence on the involvement of multiple mechanisms in photoreceptor degeneration of RP, suggesting a multi-target drug therapy is more sufficient than a single-targeted manipulation in protecting photoreceptors from degeneration in RP treatment. Neuroinflammation is suggested to be involved in pathology of glaucoma, but the mechanisms regulating microglia activation are not yet clear. We thus investigated the mechanisms underlying microglia activation in a mouse model of glaucoma. We found that microglia activation played a pathogenic role in AOH-caused retinal ganglion cell (RGC).We also demonstrated that chemokine receptorCX3CR1 in microglia played an important role in regulating microglia activation. Our findings indicate that suppressing neuroinflammation might be a therapeutic option for improving RGC survival in patients with glaucoma. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Retina - Diseases - Animal models | - |
dc.subject.lcsh | Retina - Diseases - Treatment | - |
dc.title | Exploration of drug therapy in mouse models of human retinal diseases | - |
dc.type | PG_Thesis | - |
dc.identifier.hkul | b5689280 | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Biomedical Sciences | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.5353/th_b5689280 | - |
dc.identifier.mmsid | 991018851039703414 | - |