20 results on '"Peterson, Randall T."'
Search Results
2. Parallel Reaction Monitoring reveals structure-specific ceramide alterations in the zebrafish.
- Author
-
Zhang, Tejia, Trauger, Sunia A., Vidoudez, Charles, Doane, Kim P., Pluimer, Brock R., and Peterson, Randall T.
- Subjects
LOGPERCH ,LIQUID chromatography ,HUMAN cell cycle ,FARBER disease ,LIPIDS - Abstract
Extensive characterisations of the zebrafish genome and proteome have established a foundation for the use of the zebrafish as a model organism; however, characterisation of the zebrafish lipidome has not been as comprehensive. In an effort to expand current knowledge of the zebrafish sphingolipidome, a Parallel Reaction Monitoring (PRM)-based liquid chromatography–mass spectrometry (LC–MS) method was developed to comprehensively quantify zebrafish ceramides. Comparison between zebrafish and a human cell line demonstrated remarkable overlap in ceramide composition, but also revealed a surprising lack of most sphingadiene-containing ceramides in the zebrafish. PRM analysis of zebrafish embryogenesis identified developmental stage-specific ceramide changes based on long chain base (LCB) length. A CRISPR-Cas9-generated zebrafish model of Farber disease exhibited reduced size, early mortality, and severe ceramide accumulation where the amplitude of ceramide change depended on both acyl chain and LCB lengths. Our method adds an additional level of detail to current understanding of the zebrafish lipidome, and could aid in the elucidation of structure-function associations in the context of lipid-related diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
3. Chemical Screening in Zebrafish.
- Author
-
Brady, Colleen A., Rennekamp, Andrew J., and Peterson, Randall T.
- Published
- 2016
- Full Text
- View/download PDF
4. Zebrafish as tools for drug discovery.
- Author
-
MacRae, Calum A. and Peterson, Randall T.
- Abstract
The zebrafish has become a prominent vertebrate model for disease and has already contributed to several examples of successful phenotype-based drug discovery. For the zebrafish to become useful in drug development more broadly, key hurdles must be overcome, including a more comprehensive elucidation of the similarities and differences between human and zebrafish biology. Recent studies have begun to establish the capabilities and limitations of zebrafish for disease modelling, drug screening, target identification, pharmacology, and toxicology. As our understanding increases and as the technologies for manipulating zebrafish improve, it is hoped that the zebrafish will have a key role in accelerating the emergence of precision medicine. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
5. Engineered CRISPR-Cas9 nucleases with altered PAM specificities.
- Author
-
Kleinstiver, Benjamin P., Prew, Michelle S., Tsai, Shengdar Q., Topkar, Ved V., Nguyen, Nhu T., Zheng, Zongli, Gonzales, Andrew P. W., Li, Zhuyun, Peterson, Randall T., Yeh, Jing-Ruey Joanna, Aryee, Martin J., and Joung, J. Keith
- Subjects
CRISPRS ,NUCLEOTIDE sequence ,GENOME editing ,STREPTOCOCCUS pyogenes ,STREPTOCOCCUS thermophilus ,DOUBLE-stranded RNA - Abstract
Although CRISPR-Cas9 nucleases are widely used for genome editing, the range of sequences that Cas9 can recognize is constrained by the need for a specific protospacer adjacent motif (PAM). As a result, it can often be difficult to target double-stranded breaks (DSBs) with the precision that is necessary for various genome-editing applications. The ability to engineer Cas9 derivatives with purposefully altered PAM specificities would address this limitation. Here we show that the commonly used Streptococcus pyogenes Cas9 (SpCas9) can be modified to recognize alternative PAM sequences using structural information, bacterial selection-based directed evolution, and combinatorial design. These altered PAM specificity variants enable robust editing of endogenous gene sites in zebrafish and human cells not currently targetable by wild-type SpCas9, and their genome-wide specificities are comparable to wild-type SpCas9 as judged by GUIDE-seq analysis. In addition, we identify and characterize another SpCas9 variant that exhibits improved specificity in human cells, possessing better discrimination against off-target sites with non-canonical NAG and NGA PAMs and/or mismatched spacers. We also find that two smaller-size Cas9 orthologues, Streptococcus thermophilus Cas9 (St1Cas9) and Staphylococcus aureus Cas9 (SaCas9), function efficiently in the bacterial selection systems and in human cells, suggesting that our engineering strategies could be extended to Cas9s from other species. Our findings provide broadly useful SpCas9 variants and, more importantly, establish the feasibility of engineering a wide range of Cas9s with altered and improved PAM specificities. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
6. Photochemical activation of TRPA1 channels in neurons and animals.
- Author
-
Kokel, David, Cheung, Chung Yan J, Mills, Robert, Coutinho-Budd, Jaeda, Huang, Liyi, Setola, Vincent, Sprague, Jared, Jin, Shan, Jin, Youngnam N, Huang, Xi-Ping, Bruni, Giancarlo, Woolf, Clifford J, Roth, Bryan L, Hamblin, Michael R, Zylka, Mark J, Milan, David J, and Peterson, Randall T
- Subjects
ZEBRA danio ,NEURONS ,CATIONS ,PHOTORECEPTORS ,CYSTEINE - Abstract
Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild-type zebrafish and mice. To our surprise, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in nontransgenic animals, including humans. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
7. Rapid behavior-based identification of neuroactive small molecules in the zebrafish.
- Author
-
Kokel, David, Bryan, Jennifer, Laggner, Christian, White, Rick, Cheung, Chung Yan J., Mateus, Rita, Healey, David, Kim, Sonia, Werdich, Andreas A., Haggarty, Stephen J., MacRae, Calum A., Shoichet, Brian, and Peterson, Randall T.
- Subjects
ZEBRA danio ,ALTERNATIVE treatment for mental illness ,MONOAMINE oxidase inhibitors ,MOLECULAR biology ,PHENOTYPES ,PSYCHIATRIC drugs ,PHYSIOLOGY - Abstract
Neuroactive small molecules are indispensable tools for treating mental illnesses and dissecting nervous system function. However, it has been difficult to discover novel neuroactive drugs. Here, we describe a high-throughput, behavior-based approach to neuroactive small molecule discovery in the zebrafish. We used automated screening assays to evaluate thousands of chemical compounds and found that diverse classes of neuroactive molecules caused distinct patterns of behavior. These 'behavioral barcodes' can be used to rapidly identify new psychotropic chemicals and to predict their molecular targets. For example, we identified new acetylcholinesterase and monoamine oxidase inhibitors using phenotypic comparisons and computational techniques. By combining high-throughput screening technologies with behavioral phenotyping in vivo, behavior-based chemical screens can accelerate the pace of neuroactive drug discovery and provide small-molecule tools for understanding vertebrate behavior. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
8. Discovering chemical modifiers of oncogene-regulated hematopoietic differentiation.
- Author
-
Yeh, Jing-Ruey J., Munson, Kathleen M,, Elagib, Kamaleldin E,, Goldfarb, Adam N,, Sweetser, David A,, and Peterson, Randall T,
- Subjects
HEMATOPOIETIC stem cells ,CELL differentiation ,ONCOGENES ,ANTINEOPLASTIC agents ,ZEBRA danio ,ANIMAL models in research ,CHEMICAL biology - Abstract
It has been proposed that inhibitors of an oncogene's effects on multipotent hematopoietic progenitor cell differentiation may change the properties of the leukemic stem cells and complement the clinical use of cytotoxic drugs. Using zebrafish, we developed a robust in vivo hematopoietic differentiation assay that reflects the activity of the oncogene AML1-ETO. Screening for modifiers of AML1-ETO–mediated hematopoietic dysregulation uncovered unexpected roles of COX-2– and β-catenin–dependent pathways in AML1-ETO function. This approach may open doors for developing therapeutics targeting oncogene function within leukemic stem cells. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
9. BMP type I receptor inhibition reduces heterotopic ossification.
- Author
-
Yu, Paul B., Deng, Donna Y., Lai, Carol S., Hong, Charles C., Cuny, Gregory D., Bouxsein, Mary L., Hong, Deborah W., McManus, Patrick M., Katagiri, Takenobu, Sachidanandan, Chetana, Kamiya, Nobuhiro, Fukuda, Tomokazu, Mishina, Yuji, Peterson, Randall T., and Bloch, Kenneth D.
- Subjects
FIBRODYSPLASIA ossificans progressiva ,TISSUES ,GENETIC mutation ,BONE morphogenetic proteins ,OSSIFICATION ,CELL receptors ,GLUTAMINE ,LABORATORY mice ,DISEASES - Abstract
Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues and is without known effective treatments. Affected individuals harbor conserved mutations in the ACVR1 gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2). Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I receptor kinases, LDN-193189 (ref. 6), inhibits activation of the BMP signaling effectors SMAD1, SMAD5 and SMAD8 in tissues expressing caALK2 induced by adenovirus specifying Cre (Ad.Cre). This treatment resulted in a reduction in ectopic ossification and functional impairment. In contrast to localized induction of caALK2 by Ad.Cre (which entails inflammation), global postnatal expression of caALK2 (induced without the use of Ad.Cre and thus without inflammation) does not lead to ectopic ossification. However, if in this context an inflammatory stimulus was provided with a control adenovirus, ectopic bone formation was induced. Like LDN-193189, corticosteroid inhibits ossification in Ad.Cre-injected mutant mice, suggesting caALK2 expression and an inflammatory milieu are both required for the development of ectopic ossification in this model. These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of FOP and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
10. Chemical biology and the limits of reductionism.
- Author
-
Peterson, Randall T.
- Subjects
- *
CHEMICAL biology , *BIOCHEMISTRY , *MOLECULAR biology , *SYSTEMS biology , *BIOINFORMATICS - Abstract
Chemical biology and systems biology have grown and evolved in parallel during the past decade, but the mindsets of the two disciplines remain quite different. As the inevitable intersections between the disciplines become more frequent, chemical biology has an opportunity to assimilate the most powerful ideas from systems biology. Can the integrationist mindset of systems biology liberate chemical biology from the compulsion to reduce everything to individual small molecule-target pairings? [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
11. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism.
- Author
-
Yu, Paul B, Hong, Charles C, Sachidanandan, Chetana, Babitt, Jodie L, Deng, Donna Y, Hoyng, Stefan A, Lin, Herbert Y, Bloch, Kenneth D, and Peterson, Randall T
- Subjects
EMBRYOLOGY ,IRON metabolism ,BONE morphogenetic proteins ,PHYSIOLOGY ,PHOSPHORYLATION - Abstract
Bone morphogenetic protein (BMP) signals coordinate developmental patterning and have essential physiological roles in mature organisms. Here we describe the first known small-molecule inhibitor of BMP signaling—dorsomorphin, which we identified in a screen for compounds that perturb dorsoventral axis formation in zebrafish. We found that dorsomorphin selectively inhibits the BMP type I receptors ALK2, ALK3 and ALK6 and thus blocks BMP-mediated SMAD1/5/8 phosphorylation, target gene transcription and osteogenic differentiation. Using dorsomorphin, we examined the role of BMP signaling in iron homeostasis. In vitro, dorsomorphin inhibited BMP-, hemojuvelin- and interleukin 6–stimulated expression of the systemic iron regulator hepcidin, which suggests that BMP receptors regulate hepcidin induction by all of these stimuli. In vivo, systemic challenge with iron rapidly induced SMAD1/5/8 phosphorylation and hepcidin expression in the liver, whereas treatment with dorsomorphin blocked SMAD1/5/8 phosphorylation, normalized hepcidin expression and increased serum iron levels. These findings suggest an essential physiological role for hepatic BMP signaling in iron-hepcidin homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
12. In vivo drug discovery in the zebrafish.
- Author
-
Zon, Leonard I. and Peterson, Randall T.
- Subjects
- *
ZEBRA danio , *FERTILITY , *MORPHOLOGY , *PHENOTYPES , *MAMMALS , *GENOMICS , *DRUG development - Abstract
The zebrafish has become a widely used model organism because of its fecundity, its morphological and physiological similarity to mammals, the existence of many genomic tools and the ease with which large, phenotype-based screens can be performed. Because of these attributes, the zebrafish might also provide opportunities to accelerate the process of drug discovery. By combining the scale and throughput of in vitro screens with the physiological complexity of animal studies, the zebrafish promises to contribute to several aspects of the drug development process, including target identification, disease modelling, lead discovery and toxicology. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
13. Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation.
- Author
-
Peterson, Randall T., Shaw, Stanley Y., Peterson, Travis A., Milan, David J., Zhong, Tao P., Schreiber, Stuart L., MacRae, Calum A., and Fishman, Mark C.
- Subjects
- *
ZEBRA danio , *GENETIC mutation , *GENETICS , *AORTIC coarctation , *BLOOD flow , *PHENOTYPES - Abstract
Conventional drug discovery approaches require a priori selection of an appropriate molecular target, but it is often not obvious which biological pathways must be targeted to reverse a disease phenotype1'2. Phenotype-based screens offer the potential to identify pathways and potential therapies that influence disease processes. The zebrafish mutation gridlock (grl, affecting the gene hey2) disrupts aortic blood flow in a region and physiological manner akin to aortic coarctation in humans3-5. Here we use a whole-organism, phenotype-based, small-molecule screen to discover a class of compounds that suppress the coarctation phenotype and permit survival to adulthood. These compounds function during the specification and migration of angioblasts. They act to upregulate expression of vascular endothelial growth factor (VEGF), and the activation of the VEGF pathway is sufficient to suppress the gridlock phenotype. Thus, organism-based screens allow the discovery of small molecules that ameliorate complex dysmorphic syndromes even without targeting the affected gene directly. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
14. Efficient genome editing in zebrafish using a CRISPR-Cas system.
- Author
-
Hwang, Woong Y, Fu, Yanfang, Reyon, Deepak, Maeder, Morgan L, Tsai, Shengdar Q, Sander, Jeffry D, Peterson, Randall T, Yeh, J-R Joanna, and Joung, J Keith
- Subjects
ZEBRA danio ,GENOMES ,MICROSATELLITE repeats ,ENDONUCLEASES ,ZINC-finger proteins - Abstract
In bacteria, foreign nucleic acids are silenced by clustered, regularly interspaced, short palindromic repeats (CRISPR)-CRISPR-associated (Cas) systems. Bacterial type II CRISPR systems have been adapted to create guide RNAs that direct site-specific DNA cleavage by the Cas9 endonuclease in cultured cells. Here we show that the CRISPR-Cas system functions in vivo to induce targeted genetic modifications in zebrafish embryos with efficiencies similar to those obtained using zinc finger nucleases and transcription activator-like effector nucleases. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
15. Chemical informatics and target identification in a zebrafish phenotypic screen.
- Author
-
Laggner, Christian, Kokel, David, Setola, Vincent, Tolia, Alexandra, Lin, Henry, Irwin, John J, Keiser, Michael J, Cheung, Chung Yan J, Minor, Daniel L, Roth, Bryan L, Peterson, Randall T, and Shoichet, Brian K
- Subjects
CHEMINFORMATICS ,ZEBRA danio ,PHENOTYPES ,BIOCHEMICAL genetics ,ECOLOGICAL disturbances ,CELL lines ,G protein-coupled receptor kinases - Abstract
Target identification is a core challenge in chemical genetics. Here we use chemical similarity to computationally predict the targets of 586 compounds that were active in a zebrafish behavioral assay. Among 20 predictions tested, 11 compounds had activities ranging from 1 nM to 10,000 nM on the predicted targets. The roles of two of these targets were tested in the original zebrafish phenotype. Prediction of targets from chemotype is rapid and may be generally applicable. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
16. Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation.
- Author
-
McCarroll, Matthew N., Gendelev, Leo, Kinser, Reid, Taylor, Jack, Bruni, Giancarlo, Myers-Turnbull, Douglas, Helsell, Cole, Carbajal, Amanda, Rinaldi, Capria, Kang, Hye Jin, Gong, Jung Ho, Sello, Jason K., Tomita, Susumu, Peterson, Randall T., Keiser, Michael J., and Kokel, David
- Subjects
GABA ,SEROTONIN receptors ,AMINO acid neurotransmitters ,ANESTHETICS ,ZEBRA danio ,CENTRAL nervous system depressants ,CONSCIOUS sedation - Abstract
Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity—a phenomenon known as paradoxical excitation. Previous studies have identified GABA
A receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABAA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish. Some anesthetics despite being generally associated with sedation, can also increase brain activity—a phenomenon called paradoxical excitation. The authors identified dozens of compounds that generally decrease neuronal activity, but increase activity in the caudal hindbrain of zebrafish. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
- View/download PDF
17. Targeted gene disruption in somatic zebrafish cells using engineered TALENs.
- Author
-
Sander, Jeffry D, Cade, Lindsay, Khayter, Cyd, Reyon, Deepak, Peterson, Randall T, Joung, J Keith, and Yeh, Jing-Ruey J
- Subjects
LETTERS to the editor ,ZEBRA danio ,SOMATIC cells - Abstract
A letter to the editor is presented in response to the article "Targeted Gene Disruption in Somatic Zebrafish Cells Using Engineered TALENs," by J. C. Miller and colleagues, published in the 2011 issue.
- Published
- 2011
- Full Text
- View/download PDF
18. Drug discovery: Propping up a destructive regime.
- Author
-
Peterson, Randall T.
- Subjects
- *
ANTINEOPLASTIC agents , *WNT genes , *CANCER cell proliferation , *COLON cancer treatment , *SCIENTIFIC discoveries , *CELL nuclei , *SCIENTIFIC development , *THERAPEUTICS research - Abstract
The article discusses the significance of the research study on the tankyrase involvement in Wnt signalling pathway, conducted by S. Huang. It states that the findings of the study, which emphasized the destruction of cancer cells, suggests compounds that prevent Wnt signals from reaching the cell nucleus which are potential candidates for treating colon cancer and other Wnt-dependent cancers. The author also explains that the findings of the study which discover the compound XAV939 serve as a clue for possible treatment for colon cancer.
- Published
- 2009
- Full Text
- View/download PDF
19. Novel Wnt antagonists target porcupine and Axin.
- Author
-
Yeh, Jing-Ruey J and Peterson, Randall T
- Subjects
- *
NONSTEROIDAL anti-inflammatory agents , *COLON cancer treatment , *EMBRYOLOGY , *WNT genes , *WNT proteins - Abstract
The article offers information on the small molecules that inhibit Wnt signaling by two mechanisms, giving a chance for research to improve treatment of colon cancer. It is said that Wnt signaling pathway has a role in the embryonic development. It is cited that nonsteroidal anti-inflammatory drugs (NSAIDs) have been known to inhibit Wnt signaling.
- Published
- 2009
- Full Text
- View/download PDF
20. Erratum: BMP type I receptor inhibition reduces heterotopic ossification.
- Author
-
Yu, Paul B, Deng, Donna Y, Lai, Carol S, Hong, Charles C, Cuny, Gregory D, Bouxsein, Mary L, Hong, Deborah W, McManus, Patrick M, Katagiri, Takenobu, Sachidanandan, Chetana, Kamiya, Nobuhiro, Fukuda, Tomokazu, Mishina, Yuji, Peterson, Randall T, and Bloch, Kenneth D
- Subjects
SPELLING errors ,ABSTRACTING ,ORTHOGRAPHY & spelling ,VOCABULARY - Abstract
Several corrections to the article "BMP Type I Receptor Inhibition Reduces Heterotopic Ossification," that was published in the November 30, 2008 issue, are presented.
- Published
- 2009
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.