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Reynolds, Alison
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Reynolds, Alison
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Reynolds, Alison
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Now showing 1 - 10 of 14
- PublicationThe effects of corticosteroid drugs on the visual function of zebrafishIntroduction: Glaucoma, a leading cause of blindness, is a heterogenous eye condition characterized by gradual loss of visual acuity due to degeneration of retinal ganglion cells (1). Glaucoma is an off-target effect of corticosteroids when administered intraocularly for treatment of some ocular indications (2). This study uses zebrafish to study whether a glaucoma-type disease is induced by treatment with corticosteroids by assessing the effects on retinal histology and visual function.
70 - PublicationStructure-activity relationship of a novel family of cysteinyl leukotriene receptor antagonist quinoline compounds with anti-angiogenic activity(British Pharmacological Society, 2017-04-01)
; ; ; ; ; ; ; ; ; ; ; Introduction: Previously, we identified quininib (2-[(E)-2-(quinolin-2-yl)vinyl]phenol), a cysteinyl leukotriene receptor antagonist with anti-angiogenic and anti-permeable activity (1,2). Here, we report a structure activity relationship study to more comprehensively characterise features which confer anti-angiogenic activity.21 - PublicationThe Role of Mitochondria in Optic Atrophy With Autosomal Inheritance(Frontiers Media, 2021-11-15)
; ; ; ; ; Optic atrophy (OA) with autosomal inheritance is a form of optic neuropathy characterized by the progressive and irreversible loss of vision. In some cases, this is accompanied by additional, typically neurological, extra-ocular symptoms. Underlying the loss of vision is the specific degeneration of the retinal ganglion cells (RGCs) which form the optic nerve. Whilst autosomal OA is genetically heterogenous, all currently identified causative genes appear to be associated with mitochondrial organization and function. However, it is unclear why RGCs are particularly vulnerable to mitochondrial aberration. Despite the relatively high prevalence of this disorder, there are currently no approved treatments. Combined with the lack of knowledge concerning the mechanisms through which aberrant mitochondrial function leads to RGC death, there remains a clear need for further research to identify the underlying mechanisms and develop treatments for this condition. This review summarizes the genes known to be causative of autosomal OA and the mitochondrial dysfunction caused by pathogenic mutations. Furthermore, we discuss the suitability of available in vivo models for autosomal OA with regards to both treatment development and furthering the understanding of autosomal OA pathology.17Scopus© Citations 1 - PublicationComparative ocular gene therapy: How curing inherited blindness in Briard dogs benefits everyone(2019-08-11)Laboratory animals (zebrafish, rodents, rabbits, dogs and primates) have been used for decades to model various forms of ocular disease and in the discovery and development of therapeutics. Leber congenital amaurosis (LCA, OMIM # 20400) is a family of rare, inherited, early-onset severe retinal degenerations (EOSRDs) which affects 1 in 80,000 and presents in infancy.
41Scopus© Citations 3 - PublicationPhenotype-based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis(American Society for Biochemistry and Molecular Biology, 2016-04-01)
; ; ; ; ; ; ; ; ; ; ; Retinal angiogenesis is tightly regulated to meet oxygenation and nutritional requirements. In diseases such as proliferative diabetic retinopathy and neovascular age-related macular degeneration, uncontrolled angiogenesis can lead to blindness. Our goal is to better understand the molecular processes controlling retinal angiogenesis and discover novel drugs that inhibit retinal neovascularization. Phenotype-based chemical screens were performed using the ChemBridge DiversetTM library and inhibition of hyaloid vessel angiogenesis in Tg(fli1:EGFP) zebrafish. 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol, (quininib) robustly inhibits developmental angiogenesis at 4–10 μm in zebrafish and significantly inhibits angiogenic tubule formation in HMEC-1 cells, angiogenic sprouting in aortic ring explants, and retinal revascularization in oxygen-induced retinopathy mice. Quininib is well tolerated in zebrafish, human cell lines, and murine eyes. Profiling screens of 153 angiogenic and inflammatory targets revealed that quininib does not directly target VEGF receptors but antagonizes cysteinyl leukotriene receptors 1 and 2 (CysLT1–2) at micromolar IC50 values. In summary, quininib is a novel anti-angiogenic small-molecule CysLT receptor antagonist. Quininib inhibits angiogenesis in a range of cell and tissue systems, revealing novel physiological roles for CysLT signaling. Quininib has potential as a novel therapeutic agent to treat ocular neovascular pathologies and may complement current anti-VEGF biological agents.348Scopus© Citations 29 - PublicationCan histone deacetylase inhibitors uncover novel therapeutic agents for inherited retinal dystrophies(2017-12-13)
; ; ; ; Inherited retinal dystrophies (iRDs) affect 1 in 3000 people worldwide and effective treatment options are not widely available due to the genetic and clinical heterogeneity. Recently, histone deacetylase inhibitors (HDACi) have gained attention as a potential therapeutic option based on their neuroprotective effects within the retina. However, the benefits of HDACi remains highly controversial, and their downstream mechanism of action are yet to be thoroughly elucidated. Preliminary data from studies conducted has shown that treatment of zebrafish retinal mutant with HDACi, trichostatin A (TSA), could rescue visual capacity and retinal morphology. The current study is designed to address the suitability of HDACi as therapeutic options for iRDs using zebrafish models.76 - PublicationInhibition of the Pim1 Oncogene Results in Diminished Visual Function(Public Library of Science, 2012-12-26)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Our objective was to profile genetic pathways whose differential expression correlates with maturation of visual function in zebrafish. Bioinformatic analysis of transcriptomic data revealed Jak-Stat signalling as the pathway most enriched in the eye, as visual function develops. Real-time PCR, western blotting, immunohistochemistry and in situ hybridization data confirm that multiple Jak-Stat pathway genes are up-regulated in the zebrafish eye between 3-5 days post-fertilisation, times associated with significant maturation of vision. One of the most up-regulated Jak-Stat genes is the proto-oncogene Pim1 kinase, previously associated with haematological malignancies and cancer. Loss of function experiments using Pim1 morpholinos or Pim1 inhibitors results in significant diminishment of visual behaviour and function. In summary, we have identified that enhanced expression of Jak-Stat pathway genes correlates with maturation of visual function and that the Pim1 oncogene is required for normal visual function.277Scopus© Citations 20 - PublicationProtocol for a preclinical systematic review and meta-analysis of pharmacological targeting of peroxisome proliferator-activated receptors in experimental renal injury(BMJ, 2021-11-15)
; ; ; ; ; ; ; Introduction Impaired lipid metabolism in the renal tubule plays a prominent role in the progression of renal fibrosis following acute kidney injury (AKI) and in chronic kidney disease (CKD). Peroxisome proliferator-activated receptors (PPARs) are promising druggable targets to mitigate renal fibrosis by redirecting metabolism, including restoration of fatty acid oxidation (FAO) capacity. We aim to synthesise evidence from preclinical studies of pharmacological PPAR targeting in experimental renal injury, and inform the design of future studies evaluating PPAR-mediated restoration of FAO in AKI and CKD.47Scopus© Citations 2 - PublicationInvestigation of the role of cysteinyl leukotrienes in ocular developmental angiogenesis(Association for Research in Vision and Opthalmology, 2016-09)
; ; ; ; ; ; Previously, we identified quininib (2-[(E)-2-(quinolin-2-yl)vinyl] phenol) and a related series of cysteinyl leukotriene (cysLT) receptor antagonists which inhibit hyaloid vessel development in zebrafish eyes. Here, we more comprehensively characterise the expression and function of specific cysLT signalling components in ocular developmental angiogenesis.30 - PublicationBrain-Derived Neurotrophic Factor as a Treatment Option for Retinal Degeneration(Springer, 2018-05-03)
; ; ; ; ; This review discusses the therapeutic potential of brain-derived neurotrophic factor (BDNF) for retinal degeneration. BDNF, nerve growth factor (NGF), neurotrophin 3 (NT-3) and NT-4/NT-5 belong to the neurotrophin family. These neuronal modulators activate a common receptor and a specific tropomyosin-related kinase (Trk) receptor. BDNF was identified as a photoreceptor protectant in models of retinal degeneration as early as 1992. However, development of effective therapeutics that exploit this pathway has been difficult due to challenges in sustaining therapeutic levels in the retina.181Scopus© Citations 13