19 results on '"Peterson, Randall T."'
Search Results
2. Screening Platforms for Genetic Epilepsies—Zebrafish, iPSC-Derived Neurons, and Organoids.
- Author
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Shcheglovitov, Aleksandr and Peterson, Randall T.
- Abstract
Recent advances in molecular and cellular engineering, such as human cell reprogramming, genome editing, and patient-specific organoids, have provided unprecedented opportunities for investigating human disorders in both animals and human-based models at an improved pace and precision. This progress will inevitably lead to the development of innovative drug-screening platforms and new patient-specific therapeutics. In this review, we discuss recent advances that have been made using zebrafish and human-induced pluripotent stem cell (iPSC)–derived neurons and organoids for modeling genetic epilepsies. We also provide our prospective on how these models can potentially be combined to build new screening platforms for antiseizure and antiepileptogenic drug discovery that harness the robustness and tractability of zebrafish models as well as the patient-specific genetics and biology of iPSC-derived neurons and organoids. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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3. Developing zebrafish disease models for in vivo small molecule screens.
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Lam, Pui-Ying and Peterson, Randall T
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BRACHYDANIO , *IN vivo studies , *IN vitro studies - Abstract
The zebrafish is a model organism that allows in vivo studies to be performed at a scale usually restricted to in vitro studies. As such, the zebrafish is well suited to in vivo screens, in which thousands of small molecules are tested for their ability to modify disease phenotypes in zebrafish disease models. Numerous approaches have been developed for modeling human diseases in zebrafish, including mutagenesis, transgenesis, pharmacological approaches, wounding, and exposure to infectious or cancerous agents. We review the various strategies for modeling human diseases in zebrafish and discuss important considerations when developing zebrafish models for use in in vivo small molecule screens. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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4. Development of an opioid self-administration assay to study drug seeking in zebrafish.
- Author
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Bossé, Gabriel D. and Peterson, Randall T.
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ZEBRA danio , *OPIOID abuse , *MENTAL health , *NALOXONE , *FISH as laboratory animals , *PHYSIOLOGY , *THERAPEUTICS - Abstract
The zebrafish ( Danio rerio ) has become an excellent tool to study mental health disorders, due to its physiological and genetic similarity to humans, ease of genetic manipulation, and feasibility of small molecule screening. Zebrafish have been shown to exhibit characteristics of addiction to drugs of abuse in non-contingent assays, including conditioned place preference, but contingent assays have been limited to a single assay for alcohol consumption. Using inexpensive electronic, mechanical, and optical components, we developed an automated opioid self-administration assay for zebrafish, enabling us to measure drug seeking and gain insight into the underlying biological pathways. Zebrafish trained in the assay for five days exhibited robust self-administration, which was dependent on the function of the μ-opioid receptor. In addition, a progressive ratio protocol was used to test conditioned animals for motivation. Furthermore, conditioned fish continued to seek the drug despite an adverse consequence and showed signs of stress and anxiety upon withdrawal of the drug. Finally, we validated our assay by confirming that self-administration in zebrafish is dependent on several of the same molecular pathways as in other animal models. Given the ease and throughput of this assay, it will enable identification of important biological pathways regulating drug seeking and could lead to the development of new therapeutic molecules to treat addiction. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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5. A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled Speed.
- Author
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Palchaudhuri, Rahul, Lambrecht, Michael J., Botham, Rachel C., Partlow, Kathryn C., van Ham, Tjakko J., Putt, Karson S., Nguyen, Laurie T., Kim, Seok-Ho, Peterson, Randall T., Fan, Timothy M., and Hergenrother, Paul J.
- Abstract
Summary Apoptosis is generally believed to be a process that requires several hours, in contrast to non-programmed forms of cell death that can occur in minutes. Our findings challenge the time-consuming nature of apoptosis as we describe the discovery and characterization of a small molecule, named Raptinal, which initiates intrinsic pathway caspase-dependent apoptosis within minutes in multiple cell lines. Comparison to a mechanistically diverse panel of apoptotic stimuli reveals that Raptinal-induced apoptosis proceeds with unparalleled speed. The rapid phenotype enabled identification of the critical roles of mitochondrial voltage-dependent anion channel function, mitochondrial membrane potential/coupled respiration, and mitochondrial complex I, III, and IV function for apoptosis induction. Use of Raptinal in whole organisms demonstrates its utility for studying apoptosis in vivo for a variety of applications. Overall, rapid inducers of apoptosis are powerful tools that will be used in a variety of settings to generate further insight into the apoptotic machinery. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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6. PTPMT1 Inhibition Lowers Glucose through Succinate Dehydrogenase Phosphorylation.
- Author
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Nath, Anjali K., Ryu, Justine H., Jin, Youngnam N., Roberts, Lee D., Dejam, Andre, Gerszten, Robert E., and Peterson, Randall T.
- Abstract
Summary Virtually all organisms seek to maximize fitness by matching fuel availability with energy expenditure. In vertebrates, glucose homeostasis is central to this process, with glucose levels finely tuned to match changing energy requirements. To discover new pathways regulating glucose levels in vivo, we performed a large-scale chemical screen in live zebrafish and identified the small molecule alexidine as a potent glucose-lowering agent. We found that alexidine inhibits the PTEN-like mitochondrial phosphatase PTPMT1 and that other pharmacological and genetic means of inactivating PTPMT1 also decrease glucose levels in zebrafish. Mutation of ptpmt1 eliminates the effect of alexidine, further confirming it as the glucose-lowering target of alexidine. We then identified succinate dehydrogenase (SDH) as a substrate of PTPMT1. Inactivation of PTPMT1 causes hyperphosphorylation and activation of SDH, providing a possible mechanism by which PTPMT1 coordinates glucose homeostasis. Therefore, PTPMT1 appears to be an important regulator of SDH phosphorylation status and glucose concentration. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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7. 15 years of zebrafish chemical screening.
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Rennekamp, Andrew J and Peterson, Randall T
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PHENOTYPES , *GENETIC mutation , *ZEBRA danio , *GENETIC testing , *DEVELOPMENTAL biology , *REGENERATION (Biology) - Abstract
In 2000, the first chemical screen using living zebrafish in a multi-well plate was reported. Since then, more than 60 additional screens have been published describing whole-organism drug and pathway discovery projects in zebrafish. To investigate the scope of the work reported in the last 14 years and to identify trends in the field, we analyzed the discovery strategies of 64 primary research articles from the literature. We found that zebrafish screens have expanded beyond the use of developmental phenotypes to include behavioral, cardiac, metabolic, proliferative and regenerative endpoints. Additionally, many creative strategies have been used to uncover the mechanisms of action of new small molecules including chemical phenocopy, genetic phenocopy, mutant rescue, and spatial localization strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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8. Fishing for new antimicrobials
- Author
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Mukhopadhyay, Arpita and Peterson, Randall T
- Subjects
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ANTIBIOTICS , *ANTI-infective agents , *PENICILLIN , *COMMUNICABLE diseases in animals , *ZEBRA danio - Abstract
The discovery of antibiotics and other antimicrobial agents in the 1930s is arguably the most significant therapeutic advance in medical history. Penicillin and the sulfa drugs touched off the search for and discovery of countless derivative compounds and several new antibiotic classes. However, the pace of discovery has slowed down, and there is growing appreciation that much of the low-lying fruit accessible to traditional methods of antimicrobial discovery has been harvested. Combating emerging drug-resistant strains of infectious agents may require the adoption of fresh approaches to drug target validation, small-molecule discovery and safety assessment. The recent development of several infectious disease models in zebrafish raises the possibility of a new paradigm in antimicrobial discovery. [Copyright &y& Elsevier]
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- 2006
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9. Discovery of therapeutic targets by phenotype-based zebrafish screens.
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Peterson, Randall T.
- Subjects
PHENOTYPES ,ZEBRA danio ,OLIGONUCLEOTIDES ,TARGETED drug delivery ,MOLECULES - Abstract
The easy identification of phenotypes in the transparent zebrafish embryo has enabled numerous genetic, antisense morpholino oligonucleotide, and small molecule screens. Can zebrafish screens also be used for unbiased discovery of novel drug targets? [Copyright &y& Elsevier]
- Published
- 2004
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10. Induction of reversible hemolytic anemia in living zebrafish using a novel small molecule
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Shafizadeh, Ebrahim, Peterson, Randall T., and Lin, Shuo
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ZEBRA danio , *EMBRYOS , *ERYTHROPOIESIS , *HEMOLYTIC anemia , *ANEMIA - Abstract
We used zebrafish to screen and identify small molecules that affect the process of vertebrate hematopoietic development. Zebrafish embryos were exposed to a library of 5000 synthetic compounds and screened for defects in primitive erythropoiesis. Here, we present the characterization of hemolytic anemia induced in zebrafish by the small molecule 5115318 (3-[5-methyl-furan 2-yl]-propionic acid N′-phenyl-hydrazide). This compound is capable of generating hemoglobin aggregates and Heinz bodies in red cells in vivo only. The induced anemia is reversible and treated fish recover in about 4 days. This study shows the feasibility of using zebrafish to screen for small molecules that can modulate the specific process of erythropoiesis. [Copyright &y& Elsevier]
- Published
- 2004
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11. From phenotype to mechanism after zebrafish small molecule screens.
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Rennekamp, Andrew J. and Peterson, Randall T.
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ZEBRA danio ,PHENOTYPES ,GENOTYPE-environment interaction ,MOLECULAR biology ,COMPARATIVE studies ,BIOCHEMISTRY - Abstract
Small molecule screens conducted with living zebrafish have become a commonly practiced technique for small molecule discovery. Embryonic and larval zebrafish exhibit an almost limitless range of phenotypes, from the cellular to the organismal. Consequently, small molecule screens can be designed to discover compounds modifying any of these phenotypes. The compounds discovered by zebrafish screens pose unique challenges for target identification, but the zebrafish also provides several powerful approaches for identifying targets and determining mechanisms of action. Four major approaches have been used successfully, including methods based on comparison of chemical structures, genetic phenocopy, pharmacologic phenocopy and compound affinity. These approaches will continue to facilitate target identification for compounds from zebrafish small molecule screens, and more importantly, to reveal their mechanisms of action. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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12. Changing the scale and efficiency of chemical warfare countermeasure discovery using the zebrafish.
- Author
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Peterson, Randall T. and MacRae, Calum A.
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ZEBRA danio ,CHEMICAL warfare ,DRUG development ,IN vivo toxicity testing ,ANTIDOTES ,TECHNOLOGICAL innovations - Abstract
As the number of potential chemical warfare agents grows and as the diversity of potential threat scenarios expands with nonstate actors, so a need for innovative approaches to countermeasure development has emerged. In the last few years, the utility of the zebrafish as a model organism that is amenable to high-throughput screening has become apparent and this system has been applied to the unbiased discovery of chemical warfare countermeasures. This review summarizes the in vivo screening approaches that have been used in the countermeasure discovery arena, and highlights the successes to date as well as the potential challenges in moving the field forward. Importantly, the zebrafish platform for countermeasure discovery offers a rapid response system for the development of antidotes to the continuous stream of emerging chemical warfare agents. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
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13. Drug screening in the zebrafish: an overview.
- Author
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MacRae, Calum A. and Peterson, Randall T.
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- 2013
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14. In vivo small molecule discovery in zebrafish
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Peterson, Randall T.
- Published
- 2009
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15. Neuregulin but not endothelin signaling is required for atrioventricular conduction tissue development.
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Milan, David J., Giokas, Andrea C., Peterson, Randall T., and MacRae, Calum A.
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- 2005
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16. Small molecule screen for compounds that affect vascular development in the zebrafish retina
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Kitambi, Satish S., McCulloch, Kyle J., Peterson, Randall T., and Malicki, Jarema J.
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BLOOD vessels , *ZEBRA danio , *RETINA , *ORGANISMS - Abstract
Abstract: Blood vessel formation in the vertebrate eye is a precisely regulated process. In the human retina, both an excess and a deficiency of blood vessels may lead to a loss of vision. To gain insight into the molecular basis of vessel formation in the vertebrate retina and to develop pharmacological means of manipulating this process in a living organism, we further characterized the embryonic zebrafish eye vasculature, and performed a small molecule screen for compounds that affect blood vessel morphogenesis. The screening of approximately 2000 compounds revealed four small molecules that at specific concentrations affect retinal vessel morphology but do not produce obvious changes in trunk vessels, or in the neuronal architecture of the retina. Of these, two induce a pronounced widening of vessel diameter without a substantial loss of vessel number, one compound produces a loss of retinal blood vessels accompanied by a mild increase of their diameter, and finally one other generates a severe loss of retinal vessels. This work demonstrates the utility of zebrafish as a screening tool for small molecules that affect eye vasculature and presents several compounds of potential therapeutic importance. [Copyright &y& Elsevier]
- Published
- 2009
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17. Behavioral barcoding in the cloud: embracing data-intensive digital phenotyping in neuropharmacology
- Author
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Kokel, David, Rennekamp, Andrew J., Shah, Asmi H., Liebel, Urban, and Peterson, Randall T.
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NEUROPHARMACOLOGY , *PHENOTYPES , *CODING theory , *CLOUD computing , *NEUROPSYCHIATRY , *DATA mining , *NUMERICAL analysis - Abstract
For decades, studying the behavioral effects of individual drugs and genetic mutations has been at the heart of efforts to understand and treat nervous system disorders. High-throughput technologies adapted from other disciplines (e.g., high-throughput chemical screening, genomics) are changing the scale of data acquisition in behavioral neuroscience. Massive behavioral datasets are beginning to emerge, particularly from zebrafish labs, where behavioral assays can be performed rapidly and reproducibly in 96-well, high-throughput format. Mining these datasets and making comparisons across different assays are major challenges for the field. Here, we review behavioral barcoding, a process by which complex behavioral assays are reduced to a string of numeric features, facilitating analysis and comparison within and across datasets. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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18. Structure–activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors
- Author
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Cuny, Gregory D., Yu, Paul B., Laha, Joydev K., Xing, Xuechao, Liu, Ji-Feng, Lai, Carol S., Deng, Donna Y., Sachidanandan, Chetana, Bloch, Kenneth D., and Peterson, Randall T.
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BILIARY tract , *DIGESTIVE organs , *BILE , *BILE ducts - Abstract
Abstract: A structure–activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo[1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound 13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g., plasma t 1/2 =1.6h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition. [Copyright &y& Elsevier]
- Published
- 2008
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19. Unraveling Tissue Regeneration Pathways Using Chemical Genetics.
- Author
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Mathew, Lijoy K., Sengupta, Sumitra, Kawakami, Atsushi, Andreasen, Eric A., Löhr, Christiane V., Loynes, Catherine A., Renshaw, Stephen A., Peterson, Randall T., and Tanguay, Robert L.
- Subjects
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BIOCHEMICAL genetics , *ANTI-inflammatory agents , *ADRENOCORTICAL hormones , *ANTIPYRETICS , *BIOCHEMISTRY , *MOLECULAR genetics - Abstract
Identifying the molecular pathways that are required for regeneration remains one of the great challenges of regenerative medicine. Although genetic mutations have been useful for identifying some molecular pathways, small molecule probes of regenerative pathways might offer some advantages, including the ability to disrupt pathway function with precise temporal control. However, a vertebrate regeneration model amenable to rapid throughput small molecule screening is not currently available. We report here the development of a zebrafish early life stage fin regeneration model and its use in screening for small molecules that modulate tissue regeneration. By screening 2000 biologically active small molecules, we identified 17 that specifically inhibited regeneration. These compounds include a cluster of glucocorticoids, and we demonstrate that transient activation of the glucocorticoid receptor is sufficient to block regeneration, but only if activation occurs during wound healing/blastema formation. In addition, knockdown of the glucocorticoid receptor restores regenerative capability to nonregenerative, glucocorticoid-exposed zebrafish. To test whether the classical anti-inflammatory action of glucocorticoids is responsible for blocking regeneration, we prevented acute inflammation following amputation by antisense repression of the Pu.1 gene. Although loss of Pu.1 prevents the inflammatory response, regeneration is not affected. Collectively, these results indicate that signaling from exogenous glucocorticoids impairs blastema formation and limits regenerative capacity through an acute inflammation-independent mechanism. These studies also demonstrate the feasibility of exploiting chemical genetics to define the pathways that govern vertebrate regeneration. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
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