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Helping Anxious Zebrafish Calm Down

MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish

 

CHBIOL_22_10.c1.indd

Chemistry & Biology (2015) Volume 22, Issue 10, p1335–1346

Lundegaard et al. identify therapeutic potential for anti-cancer MEK-inhibitors to treat anxiety-like cAMP-mediated behaviors in zebrafish. Targeting cAMP-MAPK cross-talk pathways broadens the range of therapeutic targets for mental health disorders. This work illustrates the importance of whole-animal phenotypic screening in anxiety drug discovery and repurposing.

Summary

Altered phosphodiesterase (PDE)-cyclic AMP (cAMP) activity is frequently associated with anxiety disorders, but current therapies act by reducing neuronal excitability rather than targeting PDE-cAMP-mediated signaling pathways. Here, we report the novel repositioning of anti-cancer MEK inhibitors as anxiolytics in a zebrafish model of anxiety-like behaviors. PDE inhibitors or activators of adenylate cyclase cause behaviors consistent with anxiety in larvae and adult zebrafish. Small-molecule screening identifies MEK inhibitors as potent suppressors of cAMP anxiety behaviors in both larvae and adult zebrafish, while causing no anxiolytic behavioral effects on their own. The mechanism underlying cAMP-induced anxiety is via crosstalk to activation of the RAS-MAPK signaling pathway. We propose that targeting crosstalk signaling pathways can be an effective strategy for mental health disorders, and advance the repositioning of MEK inhibitors as behavior stabilizers in the context of increased cAMP.

MEK-Inhibitors-Reverse-cAMP-Mediated-Anxity-in-Zebrafish_Illustration

 

Read full article here

Live imaging reveals how wound healing influences cancer

Live imaging reveals how wound healing influences cancer

Live imaging reveals how wound influences cancer

Embo.org (2015) 

Click here to read article on Embo.org 

Researchers in the United Kingdom and Denmark have studied the “see-through” larvae of zebrafish to reveal how wound healing leads to skin cancer. Live imaging shows neutrophils, the protective inflammatory cells of the body’s immune system, diverted from an induced wound to any nearby precancerous skin cells. The newly arrived neutrophils cause rapid division of these skin cells, which may cause them to progress to melanoma. The results are published in The EMBO Journal.

“Our results provide direct visual evidence of a physical link between wound-associated inflammation and the development of skin cancer,” says EMBO Member Paul Martin, Professor at Bristol University and the University of Cardiff. “White blood cells, in particular neutrophils, that typically serve as part of the body’s built-in immune system are usurped by nearby precancerous skin cells in a way that leads to the proliferation of tumour cells in our zebrafish model experimental system of human melanoma.”

Scientists have known for some time that inflammation is one of the ten hallmarks of cancer. Cancer has also been described as a “wound that does not heal.” However details about how physical damage to body tissues might influence the progress of cancer have remained scarce.

The researchers used genetically modified larvae of zebrafish to watch the relationship between wound-associated inflammation and melanoma as the cancer took hold in the living fish. The cellular events and changes were observed by live imaging with a special confocal laser-scanning microscope.

In further experiments, the researchers were also able to show that a specific type of signaling molecule released by neutrophils, prostaglandin E2, is part of the signal that drives the splurge of cell growth linked to the cancer in their experimental system. High levels of neutrophils were also detected in human clinical samples of melanomas that had been obtained from individuals whose cancers had open ulcers. Importantly, neutrophils were linked to increased proliferation of melanoma cells and poor survival, which suggests that these findings in fish may have considerable relevance to cancer patients.

The authors note that the findings of the study may have implications for cancer surgery. Minimally invasive surgery is beneficial to cancer patients in many situations and often the preferred treatment. However, particularly in cases where all cancerous tissue cannot be removed, the inflammatory response might influence the remaining cancer cells in the body. “Our studies to date suggest that several strategies might improve outcomes for patients including the possible use of therapeutics to dampen damage-induced inflammatory responses,” adds Martin.

Further work is in progress to better understand the relationship between the inflammatory response and skin cancer in the zebrafish model system. Studies are also needed to investigate what therapeutic or other strategies might bring better interventions for patients who have adverse tissue inflammation due to planned (for example biopsy or surgery) or unplanned (e.g. ulceration) tissue damage.

Full research paper can be found in The Embo Journal. Click here to read the full paper

The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer”

Nicole Antonio, Marie Louise Bønnelykke-Behrndtz, Laura Ward, John Collin, Ib Jarle Christensen, Torben Steiniche, Henrik Schmidt, Yi Feng, Paul Martin

DMM Travel Grants

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DMM Travel Grants Available

Are you an early career scientist who is interested in attending a meeting or course relevant to the journal Disease Models & Mechanisms during 2015?

The Company of Biologists Grants Committee has allocated DMM with £10,000 to provide travel funds to conferences or courses for individuals working in the field of DMM. DMM applications are currently limited to travel that will be completed by the end of 2015.

Please visit the DMM website for further details on how to apply: DMM Travel Grants

Meeting Report: Zebrafish Disease Models Conference 8 in Boston

Meeting Report: Zebrafish Disease Models Conference 8 in Boston

Amrita Mandal, The Node. 4th September 2015

I was fortunate to attend the 8th Annual Zebrafish Disease Models (ZDM) meeting in Boston (24th Aug-27th Aug) organized by the Zebrafish Disease Models Society (ZDMS). The aim of the meeting was to foster interaction among researchers working in wide array of human diseases such as cancer, muscle disorders, gastrointestinal diseases, cardiovascular, neural disorders and hematological abnormalities with a common theme of using zebrafish as model system. The organizing committee did a wonderful job in inviting a thoughtful list of speakers, which included graduate students, postdocs, young and established PIs. All the talks were followed by thought provoking questions and constructive suggestions.

I was thrilled to learn the advantages of using zebrafish as a model to study life-threatening diseases. Zebrafish being transparent, it is possible to image what happens when development goes wrong at a very high resolution in vivo, which was presented through stunning images and videos by the presenters. Cool videos such as cancer cell escaping the vascular system and the cute fish in a tank learning to behave in socially approved ways after treatment with the drug of interest will remain in my memory for a long time. It was also amazing to learn how the field not only adapted the cutting edge CRISPR genome editing technology but also trying to fine tune it for better use (tissue specific CRISPR, CRISPR-repressor fusion). There was a session called lightning talks (5min each speaker) that featured the highlights of the selected trainees work, kind of a trailer of a movie. Later those trainees also got a chance to present posters to further explain their research in more detail. The poster session showcased great science using cutting edge techniques which altogether emphasized the fact that study of developmental processes with therapeutic approach is the path to be taken.

There was a Meet-the-Expert lunch session one day where we had a chance for an informal chat with the pioneers of the field. We got advice on different stages of our scientific career, how to become the ‘happy’ postdoc they would like to hire, lab dynamics to keep in mind when setting up your own lab and alternative careers were some of the topics discussed. Another key point of the conference was ‘Research Interest Groups’ where we had the opportunity to attend a close-knit group of researchers working a similar field. I attended the cardiac and muscle group. Many important topics were discussed, bottom line being we should keep working on promoting the sense of community by sharing information about antibodies, reagents and transgenic fish lines.

The conference also had three excellent keynote speakers. Dr. Ross Keegan’s eloquent keynote talk emphasized taking a holistic approach to treat diseases with the use of complex drugs and personalized medicines. Presence of Dr. Mark Fishman from Novartis during the conference dinner made things extra special. He delivered an engaging talk on some of his recent work using zebrafish to study social behavior. The last keynote talk was from Dr. Amy Wagers, she again emphasized how using zebrafish can significantly reduce to time from lab to clinic.

Some of the fun activities were, a mixer on Day 1 at the local Yard House where I met old friends and made some awesome new fish friends. On day 2 there was free time in the afternoon for activities in Boston. Since it’s always been my dream to visit Harvard I took the time to go for a walking tour of Harvard University. Every second on the campus was inspiring.

All together it was a fantastic gathering showcasing the power of zebrafish as a model to solve bigger questions. Four days surrounded by the pioneers in the field at the heart of science, Harvard was a dream come true for me. I came back as a more confident and passionate graduate student to continue doing science with a purpose for a better world.
To keep up with this being an international society, next year’s conference will be in Singapore in October 2016. For more information or to become a member of this awesome society please visit http://zdmsociety.org

Article originally posted in The Node – read article

Tecniplast launched new breeding system during the 9th European Zebrafish Meeting in Oslo, Norway

Tecniplast launched new breeding system during the 9th European Zebrafish Meeting in Oslo, Norway

Sponsored content

Tecniplast Aquatic Solutions launched the latest innovation in breeding systems for zebrafish during the 9th European Zebrafish Meeting in Oslo, Norway: the iSpawn-S.

iSpawn-S is a 20-liter water capacity spawning system that allows researchers to collect embryos in batches of thousands at one time. This solution came to market in response to t investigators’ need for smaller more flexible breeding systems to accommodate their research demands in any-size project or facility. Whether it is research that focuses on cellular, genetics, physiological, behavioral or toxicological studies, the new iSpawn-S offers the flexibility of multiple configurations to efficiently produce batches of embryos based upon each lab’s needs.

The concept behind the i-Spawn-S promotes efficiency and flexibility and has been successfully tested by experts in the field. This convenient bench top size offers the advantages of great ergonomics and ease of use.

i-Spawn-S completes Tecniplast’s family of breeding systems, which comprises the original iSpawn (for extensive embryo production) and the widest selection of breeding tanks in the market. Altogether, this is the largest and most complete offering of breeding systems available for zebrafish research. For information, contact info@tecniplastusa.com

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Zebrafish develop system that may improve bone marrow transplant

Zebrafish develop system that may improve bone marrow transplant

Binder, V. (2015). Zebrafish develop system that may improve bone marrow transplant. Boston Children’s Hospital.

 

Nature Cover 23 July 2015

Leonard Zon, MD, Grousbeck Professor of Pediatric Medicine at Harvard Medical School, Investigator at Howard Hughes Medical Institute, Director of the Stem Cell Program, Children’s Hospital Boston, and colleagues have developed a novel competitive marrow transplantation system in adult zebrafish in which engraftment is measured by in vivo fluorescence imaging of the kidney — the adult haematopoietic site.

Using this model to screen for engraftment enhancing activity, the authors identified epoxyeicostrienoic acids, including 11,12-epoxyeicosatrienoic acid (EET), as agents able to enhance engraftment and HSPC specification through the activation of a transcription factor Runx1-mediated expression program. This effect of EET is conserved in mice, indicating possible clinical potential for EET to promote bone marrow transplants.

The findings have been published in the July 23, 2015 issue of Nature. The cover picture of this issue shows two donor fish in red, one in green, and two recipient casper fish with kidneys in red and green to depict chimeric engraftment, as described in their article (photographic work by Vera Binder, MD, Boston Children’s Hospital, graphical work by Ellen van Rooijen, PhD, Boston Children’s Hospital).

Keystone Review

keystone

 

Keystone Symposium on DNA Methylation and Epigenomics – Zebrafish Highlights

March 29 – April 3, 2015

Brandon Kent
Graduate student, Sadler and Walsh laboratories, Icahn School of Medicine at Mount Sinai, USA

Heritable, covalent (“epigenetic”) modification of DNA and the core histone proteins is a central tenet vital to cellular specification, differentiation, and an organism’s development and survival. The join Keystone Symposium on DNA Methylation (http://www.keystonesymposia.org/15Z1) and Epigenomics (March 29th – April 3rd, 2015, Keystone CO) focused on providing the latest insights regarding epigenetic regulation of development, cancer, and application to advanced diagnostics and possible clinical application.

The zebrafish has emerged as a prominent model with regard to studying epigenetic regulation of early embryonic development. Research has been increasingly focused on epigenetic patterning of the zebrafish genome. This joint Keystone Symposium featured work from several prominent zebrafish laboratories.

Members of the Cairns group (University of Utah School of Medicine) presented work regarding epigenetic patterning of the zebrafish zygote to promote the formation of transcriptionally permissive, poised, and repressive domains across the genome in an effort to prime the embryo for proper zygotic genome activation. Work done by the Lister group at the University of Western Australia focused on the role of TET-family proteins in mediating DNA demethylation during development. The Sadler group presented their work on the epigenetic regulator, Uhrf1 and in two posters defined a critical role for this gene in in both the pre-gastrula embryo and at later developmental stages. Most exciting was a workshop previewing the Epigenome Browser (http://epigenomegateway.wustl.edu/browser/) designed by Ting Wang’s group at Washington University in St. Louis. In this comprehensive and user friendly portal to the epigenome, there are datasets of methylation and RNAseq analysis across early embryonic stages and from some adult tissue.

Critically, the zebrafish model system can be utilized to elucidate epigenetic mechanisms underlying embryonic development and cancer, especially in relation to human disease, that other model systems cannot provide. With regard to the high profile and impressive work presented at the Keystone Symposium, the benefits of in vivo modeling in the zebrafish were readily apparent and appreciated.

Zebrafish make their own sunscreen

Zebrafish make their own sunscreen

Osborn, R.A., Almabruk, K.H., Holzwarth, G., Asamizu, S., LaDu, J., Kean, K.M., Karplus, P.A., Tanguay, R.L., Bakalinsky, A.T., Mahmud, T. (2015). De novo synthesis of a sunscreen compound in vertebrates. eLIFE.

A compound known as gadusol is responsible for protecting many animals, like the zebrafish, from the sun’s harmful ultraviolet radiation, a new study from Oregon State University finds.

Researchers originally believed that the zebrafish obtained gadusol from eating algae, which has long been known to naturally produce the compound. As it turns out, many fish, amphibians, birds and reptiles seem to have developed the ability to produce gadusol through “natural genetic engineering”.

“The ability to make gadusol, which was first discovered in fish eggs, clearly has some evolutionary value to be found in so many species,” remarked study lead author Taifo Mahmud. “We know it provides UV-B protection, it makes a pretty good sunscreen. But there may also be roles it plays as an antioxidant, in stress response, embryonic development and other functions.”

Mahmud and his team also discovered a way to produce high volumes of gadusol from yeast, which could potentially be applied to commercial sunscreens. Mahmud also notes that ingestion of gadusol could possibly provide a sunscreen that protects the body from the inside.

More from Oregon State University: http://oregonstate.edu/ua/ncs/archives/2015/may/no-lotions-needed-many-animal-species-produce-their-own-sunscreen

Read full research here: http://elifesciences.org/content/elife/4/e05919.full.pdf