Drug Screening to Treat Early-Onset Eye Diseases

Zhang, Liyun; Chong, Leelyn; Cho, Jin; Liao, Pin-Chao; Shen, Feichen; Leung, Yiu-Wing

doi:10.1097/apo.0b013e31827a9969

Cited by 10 publications

(10 citation statements)

References 123 publications

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“…The VSR has proven to be a powerful assay to implicate gene function in vision and for testing diseaseassociated alleles; however, the VSR assay is typically performed one larvae at a time, making it time-consuming (Baye et al, 2011;Pretorius et al, 2011;DeLuca et al, 2016). Some visual assays, such as the VMR, have been successfully automated (Zhang et al, 2012;Gao et al, 2014;Spulber et al, 2014). However, a VMR assay can take several hours to perform, limiting the amount of fish that can be tested in one day.…”

Section: Introductionmentioning

confidence: 99%

Automated, high‐throughput, in vivo analysis of visual function using the zebrafish

Scott

Marsden

Slusarski

2016

Developmental Dynamics

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Background Modern genomics has enabled the identification of an unprecedented number of genetic variants, which in many cases are extremely rare, associated with blinding disorders. A significant challenge will be determining the pathophysiology of each new variant. The zebrafish is an excellent model for the study of inherited diseases of the eye. By 5 days-post-fertilization (dpf) they have quantifiable behavioral responses to visual stimuli. However, visual behavior assays can take several hours to perform or can only be assessed one fish at a time. Results To increase the throughput for vision assays, we used the Viewpoint Zebrabox to automate the visual startle response and created software, Visual Interrogation of Zebrafish Manipulations (VIZN), to automate data analysis. This process allows 96 zebrafish larvae to be tested and resultant data to be analyzed in under 35 minutes. We validated this system by disrupting function of a gene necessary for photoreceptor differentiation and observing decreased response to visual stimuli. Conclusions This automated method along with VIZN allows rapid, high-throughput, in vivo testing of zebrafish’s ability to respond to light/dark stimuli. This allows the rapid analysis of novel genes involved in visual function by morpholino, CRISPRS, or small molecule drug screens.

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Section: Introductionmentioning

confidence: 99%

Automated, high‐throughput, in vivo analysis of visual function using the zebrafish

Scott

Marsden

Slusarski

2016

Developmental Dynamics

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“…To illustrate these challenges, we will describe a popular high-throughput analysis of larval fish behaviour: the visual motor response (VMR). This response is a locomotor behaviour stimulated by drastic light onset or offset [ 5 , 12 – 14 ]. In a typical VMR experiment, zebrafish larvae are arranged in a 96-well plate, isolated from environmental light in a lightproof chamber, and stimulated by controlled white light.…”

Section: Introductionmentioning

confidence: 99%

“…The first step of analysis is to visualize the collected data in a plot. Typically, the activity values are averaged across the same type of sample, and plotted against time to illustrate the general behavioral profile of the animals [ 5 , 14 ]. In this case, the resulting locomotor activity is often reported as activity value per unit time.…”

Section: Introductionmentioning

confidence: 99%

Statistical Analysis of Zebrafish Locomotor Response

et al. 2015

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Zebrafish larvae display rich locomotor behaviour upon external stimulation. The movement can be simultaneously tracked from many larvae arranged in multi-well plates. The resulting time-series locomotor data have been used to reveal new insights into neurobiology and pharmacology. However, the data are of large scale, and the corresponding locomotor behavior is affected by multiple factors. These issues pose a statistical challenge for comparing larval activities. To address this gap, this study has analyzed a visually-driven locomotor behaviour named the visual motor response (VMR) by the Hotelling’s T-squared test. This test is congruent with comparing locomotor profiles from a time period. Different wild-type (WT) strains were compared using the test, which shows that they responded differently to light change at different developmental stages. The performance of this test was evaluated by a power analysis, which shows that the test was sensitive for detecting differences between experimental groups with sample numbers that were commonly used in various studies. In addition, this study investigated the effects of various factors that might affect the VMR by multivariate analysis of variance (MANOVA). The results indicate that the larval activity was generally affected by stage, light stimulus, their interaction, and location in the plate. Nonetheless, different factors affected larval activity differently over time, as indicated by a dynamical analysis of the activity at each second. Intriguingly, this analysis also shows that biological and technical repeats had negligible effect on larval activity. This finding is consistent with that from the Hotelling’s T-squared test, and suggests that experimental repeats can be combined to enhance statistical power. Together, these investigations have established a statistical framework for analyzing VMR data, a framework that should be generally applicable to other locomotor data with similar structure.

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“…VMR is currently performed using larvae, and may be more suitable for screening drugs for early-onset RD [133]. In this sense, OKR may be more suitable for screening drugs for late onset retinal diseases, as it can be performed on adult fish.…”

Section: Current Issues and Developments Of Vmr For Drug Discoverymentioning

confidence: 99%

Utilizing Zebrafish Visual Behaviors in Drug Screening for Retinal Degeneration

Ganzen

Venkatraman

Pang

et al. 2017

IJMS

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Zebrafish are a popular vertebrate model in drug discovery. They produce a large number of small and rapidly-developing embryos. These embryos display rich visual-behaviors that can be used to screen drugs for treating retinal degeneration (RD). RD comprises blinding diseases such as Retinitis Pigmentosa, which affects 1 in 4000 people. This disease has no definitive cure, emphasizing an urgency to identify new drugs. In this review, we will discuss advantages, challenges, and research developments in using zebrafish behaviors to screen drugs in vivo. We will specifically discuss a visual-motor response that can potentially expedite discovery of new RD drugs.

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Drug Screening to Treat Early-Onset Eye Diseases

Cited by 10 publications

References 123 publications

Automated, high‐throughput, in vivo analysis of visual function using the zebrafish

Automated, high‐throughput, in vivo analysis of visual function using the zebrafish

Statistical Analysis of Zebrafish Locomotor Response

Utilizing Zebrafish Visual Behaviors in Drug Screening for Retinal Degeneration

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