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  1. Article ; Online: Drug screening with zebrafish visual behavior identifies carvedilol as a potential treatment for an autosomal dominant form of retinitis pigmentosa.

    Ganzen, Logan / Ko, Mee Jung / Zhang, Mengrui / Xie, Rui / Chen, Yongkai / Zhang, Liyun / James, Rebecca / Mumm, Jeff / van Rijn, Richard M / Zhong, Wenxuan / Pang, Chi Pui / Zhang, Mingzhi / Tsujikawa, Motokazu / Leung, Yuk Fai

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 11432

    Abstract: Retinitis Pigmentosa (RP) is a mostly incurable inherited retinal degeneration affecting approximately 1 in 4000 individuals globally. The goal of this work was to identify drugs that can help patients suffering from the disease. To accomplish this, we ... ...

    Abstract Retinitis Pigmentosa (RP) is a mostly incurable inherited retinal degeneration affecting approximately 1 in 4000 individuals globally. The goal of this work was to identify drugs that can help patients suffering from the disease. To accomplish this, we screened drugs on a zebrafish autosomal dominant RP model. This model expresses a truncated human rhodopsin transgene (Q344X) causing significant rod degeneration by 7 days post-fertilization (dpf). Consequently, the larvae displayed a deficit in visual motor response (VMR) under scotopic condition. The diminished VMR was leveraged to screen an ENZO SCREEN-WELL REDOX library since oxidative stress is postulated to play a role in RP progression. Our screening identified a beta-blocker, carvedilol, that ameliorated the deficient VMR of the RP larvae and increased their rod number. Carvedilol may directly on rods as it affected the adrenergic pathway in the photoreceptor-like human Y79 cell line. Since carvedilol is an FDA-approved drug, our findings suggest that carvedilol can potentially be repurposed to treat autosomal dominant RP patients.
    MeSH term(s) Animals ; Animals, Genetically Modified/genetics ; Animals, Genetically Modified/metabolism ; Behavior, Animal/drug effects ; Cell Line ; Drug Evaluation, Preclinical ; Genetic Diseases, Inborn/drug therapy ; Genetic Diseases, Inborn/genetics ; Genetic Diseases, Inborn/metabolism ; Humans ; Mutation ; Retinal Rod Photoreceptor Cells ; Retinitis Pigmentosa/drug therapy ; Retinitis Pigmentosa/genetics ; Retinitis Pigmentosa/metabolism ; Rhodopsin/genetics ; Rhodopsin/metabolism ; Transgenes ; Vision, Ocular/drug effects ; Vision, Ocular/immunology ; Zebrafish/genetics ; Zebrafish/metabolism
    Chemical Substances Rhodopsin (9009-81-8)
    Language English
    Publishing date 2021-06-01
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-89482-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Utilizing Zebrafish Visual Behaviors in Drug Screening for Retinal Degeneration.

    Ganzen, Logan / Venkatraman, Prahatha / Pang, Chi Pui / Leung, Yuk Fai / Zhang, Mingzhi

    International journal of molecular sciences

    2017  Volume 18, Issue 6

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Animals ; Disease Models, Animal ; Drug Evaluation, Preclinical/methods ; Retina/drug effects ; Retina/pathology ; Retinal Degeneration/drug therapy ; Retinal Degeneration/pathology ; Vision, Ocular/drug effects ; Zebrafish/physiology
    Language English
    Publishing date 2017-06-02
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms18061185
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A critical evaluation of TRPA1-mediated locomotor behavior in zebrafish as a screening tool for novel anti-nociceptive drug discovery.

    Ko, Mee Jung / Ganzen, Logan C / Coskun, Emre / Mukadam, Arbaaz A / Leung, Yuk Fai / van Rijn, Richard M

    Scientific reports

    2019  Volume 9, Issue 1, Page(s) 2430

    Abstract: Current medications inadequately treat the symptoms of chronic pain experienced by over 50 million people in the United States, and may come with substantial adverse effects signifying the need to find novel treatments. One novel therapeutic target is ... ...

    Abstract Current medications inadequately treat the symptoms of chronic pain experienced by over 50 million people in the United States, and may come with substantial adverse effects signifying the need to find novel treatments. One novel therapeutic target is the Transient Receptor Potential A1 channel (TRPA1), an ion channel that mediates nociception through calcium influx of sensory neurons. Drug discovery still relies heavily on animal models, including zebrafish, a species in which TRPA1 activation produces hyperlocomotion. Here, we investigated if this hyperlocomotion follows zebrafish TRPA1 pharmacology and evaluated the strengths and limitations of using TRPA1-mediated hyperlocomotion as potential preclinical screening tool for drug discovery. To support face validity of the model, we pharmacologically characterized mouse and zebrafish TRPA1 in transfected HEK293 cells using calcium assays as well as in vivo. TRPA1 agonists and antagonists respectively activated or blocked TRPA1 activity in HEK293 cells, mice, and zebrafish in a dose-dependent manner. However, our results revealed complexities including partial agonist activity of TRPA1 antagonists, bidirectional locomotor activity, receptor desensitization, and off-target effects. We propose that TRPA1-mediated hyperlocomotion in zebrafish larvae has the potential to be used as in vivo screening tool for novel anti-nociceptive drugs but requires careful evaluation of the TRPA1 pharmacology.
    MeSH term(s) Animals ; Drug Discovery ; HEK293 Cells ; Humans ; Locomotion/drug effects ; Locomotion/genetics ; Male ; Mice ; Nociception/drug effects ; Nociceptive Pain/drug therapy ; Nociceptive Pain/genetics ; Nociceptive Pain/pathology ; TRPA1 Cation Channel/antagonists & inhibitors ; TRPA1 Cation Channel/genetics ; Zebrafish/genetics ; Zebrafish/growth & development ; Zebrafish Proteins/antagonists & inhibitors ; Zebrafish Proteins/genetics
    Chemical Substances TRPA1 Cation Channel ; Zebrafish Proteins ; trpa1a protein, zebrafish
    Language English
    Publishing date 2019-02-20
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-019-38852-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A critical evaluation of TRPA1-mediated locomotor behavior in zebrafish as a screening tool for novel anti-nociceptive drug discovery

    Mee Jung Ko / Logan C. Ganzen / Emre Coskun / Arbaaz A. Mukadam / Yuk Fai Leung / Richard M. van Rijn

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 11

    Abstract: Abstract Current medications inadequately treat the symptoms of chronic pain experienced by over 50 million people in the United States, and may come with substantial adverse effects signifying the need to find novel treatments. One novel therapeutic ... ...

    Abstract Abstract Current medications inadequately treat the symptoms of chronic pain experienced by over 50 million people in the United States, and may come with substantial adverse effects signifying the need to find novel treatments. One novel therapeutic target is the Transient Receptor Potential A1 channel (TRPA1), an ion channel that mediates nociception through calcium influx of sensory neurons. Drug discovery still relies heavily on animal models, including zebrafish, a species in which TRPA1 activation produces hyperlocomotion. Here, we investigated if this hyperlocomotion follows zebrafish TRPA1 pharmacology and evaluated the strengths and limitations of using TRPA1-mediated hyperlocomotion as potential preclinical screening tool for drug discovery. To support face validity of the model, we pharmacologically characterized mouse and zebrafish TRPA1 in transfected HEK293 cells using calcium assays as well as in vivo. TRPA1 agonists and antagonists respectively activated or blocked TRPA1 activity in HEK293 cells, mice, and zebrafish in a dose-dependent manner. However, our results revealed complexities including partial agonist activity of TRPA1 antagonists, bidirectional locomotor activity, receptor desensitization, and off-target effects. We propose that TRPA1-mediated hyperlocomotion in zebrafish larvae has the potential to be used as in vivo screening tool for novel anti-nociceptive drugs but requires careful evaluation of the TRPA1 pharmacology.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2019-02-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: 2217

    Logan Ganzen / Chi Pui Pang / Mingzhi Zhang / Motokazu Tsujikawa / Yuk Fai Leung

    Journal of Clinical and Translational Science, Vol 1, Pp 3-

    2017  Volume 4

    Abstract: OBJECTIVES/SPECIFIC AIMS: Retinitis pigmentosa (RP) is a hereditary retinal degeneration disease that affects ~1 in 4000 individuals globally, and there are currently no effective treatment options available. In order to identify potential drug ... ...

    Abstract OBJECTIVES/SPECIFIC AIMS: Retinitis pigmentosa (RP) is a hereditary retinal degeneration disease that affects ~1 in 4000 individuals globally, and there are currently no effective treatment options available. In order to identify potential drug treatments, we optimized our existing a behavioral assay around a transgenic zebrafish carrying a truncated human rhodopsin transgene [Tg(rho:Hsa.RH1_Q344X)]. This line was also crossed with the Tg(-3.7rho:EGFP) reporter for rod visualization. The Q344X larvae experiences significant rod photoreceptor death by 7 days postfertilization (dpf) (Nakao et al., 2012). METHODS/STUDY POPULATION: To assess the vision of the Q344X zebrafish, the VMR assay was run under a dim-light condition based on recorded rod b-waves in larval fish (Moyano et al., 2013) and the minimum cone activation threshold in mice (Cachafeiro et al., 2010). Specifically, Q344X and control larvae at 7 dpf were placed into a 96-well plate and acclimated to a dim-light source (1.802e-05 μ W/cm2 at 500 nm) for 1 hour. The VMR was tracked and quantified during light offset. The total distance traveled was averaged and analyzed at 1 second poststimulus. Retinas were dissected from Q344X and control larvae and whole-mounted to validate the rod degeneration in the Q344X model. RESULTS/ANTICIPATED RESULTS: We found that the Q344X larvae displayed an attenuated VMR (0.121±0.041 cm) to the dim-light offset as compared with the control larvae (0.2751±0.038 cm) (two-sample t-test; p-value=4.619e-14, n=19). Analysis of whole-mounted retinae indicated significant rod degeneration at 7 dpf compared with controls (control: 87 rods/retina, Q344X: 9.3 rods/retina, Welch two-sample t-test, p-value=1.4e4). It is unlikely that the cones of the zebrafish contributed to this VMR since the light intensity of the assay was below the cone detection threshold of mice. As the only apparent difference between the 2 groups of larvae is significant rod degeneration, it can be concluded that the behavioral phenotype was a result of the ...
    Keywords Medicine ; R
    Language English
    Publishing date 2017-09-01T00:00:00Z
    Publisher Cambridge University Press
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Drug screening with zebrafish visual behavior identifies carvedilol as a potential treatment for an autosomal dominant form of retinitis pigmentosa

    Logan Ganzen / Mee Jung Ko / Mengrui Zhang / Rui Xie / Yongkai Chen / Liyun Zhang / Rebecca James / Jeff Mumm / Richard M. van Rijn / Wenxuan Zhong / Chi Pui Pang / Mingzhi Zhang / Motokazu Tsujikawa / Yuk Fai Leung

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 14

    Abstract: Abstract Retinitis Pigmentosa (RP) is a mostly incurable inherited retinal degeneration affecting approximately 1 in 4000 individuals globally. The goal of this work was to identify drugs that can help patients suffering from the disease. To accomplish ... ...

    Abstract Abstract Retinitis Pigmentosa (RP) is a mostly incurable inherited retinal degeneration affecting approximately 1 in 4000 individuals globally. The goal of this work was to identify drugs that can help patients suffering from the disease. To accomplish this, we screened drugs on a zebrafish autosomal dominant RP model. This model expresses a truncated human rhodopsin transgene (Q344X) causing significant rod degeneration by 7 days post-fertilization (dpf). Consequently, the larvae displayed a deficit in visual motor response (VMR) under scotopic condition. The diminished VMR was leveraged to screen an ENZO SCREEN-WELL REDOX library since oxidative stress is postulated to play a role in RP progression. Our screening identified a beta-blocker, carvedilol, that ameliorated the deficient VMR of the RP larvae and increased their rod number. Carvedilol may directly on rods as it affected the adrenergic pathway in the photoreceptor-like human Y79 cell line. Since carvedilol is an FDA-approved drug, our findings suggest that carvedilol can potentially be repurposed to treat autosomal dominant RP patients.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  7. Article ; Online: Functional Profiling of Transcription Factor Genes in

    Carrillo, Alexander J / Schacht, Patrick / Cabrera, Ilva E / Blahut, Johnathon / Prudhomme, Loren / Dietrich, Sarah / Bekman, Thomas / Mei, Jennifer / Carrera, Cristian / Chen, Vivian / Clark, Isaiah / Fierro, Gerardo / Ganzen, Logan / Orellana, Jose / Wise, Shelby / Yang, Kevin / Zhong, Hui / Borkovich, Katherine A

    G3 (Bethesda, Md.)

    2017  Volume 7, Issue 9, Page(s) 2945–2956

    Abstract: Regulation of gene expression by DNA-binding transcription factors is essential for proper control of growth and development in all organisms. In this study, we annotate and characterize growth and developmental phenotypes for transcription factor genes ... ...

    Abstract Regulation of gene expression by DNA-binding transcription factors is essential for proper control of growth and development in all organisms. In this study, we annotate and characterize growth and developmental phenotypes for transcription factor genes in the model filamentous fungus
    MeSH term(s) Computational Biology/methods ; Fungal Proteins/genetics ; Gene Expression Profiling ; Genetic Association Studies ; Genome, Fungal ; Genomics/methods ; Molecular Sequence Annotation ; Mutation ; Neurospora crassa/genetics ; Neurospora crassa/metabolism ; Phenotype ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcriptome
    Chemical Substances Fungal Proteins ; Transcription Factors
    Language English
    Publishing date 2017--07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2629978-1
    ISSN 2160-1836 ; 2160-1836
    ISSN (online) 2160-1836
    ISSN 2160-1836
    DOI 10.1534/g3.117.043331
    Database MEDical Literature Analysis and Retrieval System OnLINE

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