Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Zebrafish provide insights into causes and treatment of human diseases

09.07.2012
Zebrafish, popular as aquarium fish, now have an important place in research labs as a model organism for studying human diseases.

At the 2012 International Zebrafish Development Conference, held June 20-24 in Madison, Wisconsin, numerous presentations highlighted the utility of the zebrafish for examining the basic biological mechanisms underlying human disorders and identifying potential treatment approaches for an impressive array of organ and systemic diseases.

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), while rarely fatal, can have a substantial negative impact on an individual's quality of life due to abdominal pain, diarrhea, vomiting, bleeding, and severe cramps. The causes of this chronic inflammatory disorder are largely unknown and existing treatments, usually anti-inflammatory drugs, are often not effective. In addition, IBD is often associated with increased risk of developing intestinal cancer.

Researchers from the University of Pittsburgh are using zebrafish to study the biological mechanisms that lead to intestinal inflammation, as often seen in IBD, providing additional understanding that may allow development of better therapies. Prakash Thakur, a research associate working with Nathan Bahary, M.D., Ph.D., described a mutant zebrafish strain that shows many pathological characteristics similar to IBD, including inflammation, abnormal villous architecture, disorganized epithelial cells, increased bacterial growth and high numbers of dying cells in the intestine. "Most of the hallmark features of the disease are seen in this mutant. We are utilizing this fish as a tool to unravel fundamental mechanisms of intestinal pathologies that may contribute to intestinal inflammatory disorders, " Mr. Thakur said.

The fish have a genetic mutation that disrupts de novo synthesis of an important signaling molecule called phosphatidylinositol (PI). The lack of de novo PI synthesis, Mr. Thakur and his colleagues found, leads to chronic levels of cellular stress, particularly the endoplasmic reticum stress and, ultimately, inflammation. Drugs or other interventions targeting the cellular stress response pathway, rather than just inflammation, helped restore a healthy intestinal structure and increase cell survival in the fish intestine, suggesting this mechanism as a potential therapeutic target for patients with inflammatory disorders, including IBD.

Doxorubicin-Induced Heart Failure

Doxorubicin is a potent chemotherapy drug used to treat many types of cancer, including leukemia, lymphoma, carcinoma, soft tissue sarcoma, and bladder, breast, lung, stomach and ovarian cancers. Unfortunately, drug-induced cardiomyopathy is a common side effect and can lead to heart failure in cancer patients, not only during treatment, but months or years later.

"We hope to identify some drug which only blocks the side effect of doxorubicin but preserves the therapeutic effect," said Yan Liu, Ph.D., a postdoctoral researcher working in Dr. Randall Peterson's lab at the Massachusetts General Hospital.

Dr. Liu developed a zebrafish model of doxorubicin-induced cardiomyopathy. The fish experience heart failure within two days of treatment with symptoms similar to those seen in humans, including fewer heart muscle cells, ventricular collapse, and ineffective heartbeats.

The researchers used the model to screen through thousands of potential drug compounds and identified two – visnagin and diphenylurea – that both improved cardiac function and reduced doxorubicin-induced cell death in the heart. Importantly, both compounds specifically protected heart tissue, but not tumor cells, from the toxic effects of doxorubicin. Both seem to act through the suppression of a particular signaling pathway, the c-Jun N-terminal kinase pathway, in the heart cells but not tumor cells.

Dr. Liu also reported promising preliminary results with mice showing reduced cell death and improved cardiac function, indicating that these compounds may also be active in mammals and giving hope for therapies that specifically treat doxorubicin's side effects without negating its anti-tumor activity.

Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a group of progressive neurodegenerative diseases that affect the nerves in the spinal cord that control muscles, leading to weakness, movement difficulties, poor posture, and trouble breathing and eating.

SMA is linked to mutations in a specific motor neuron survival gene, SMN1. Though mouse studies have reported immature and ineffective synaptic connections between motor neurons and muscles, little is known about the molecular mechanisms leading to those problems or how they might be fixed.

Graduate student Kelvin See, working with Associate Professor Christoph Winkler, Ph.D., at the National University of Singapore used zebrafish with activity-sensitive fluorescence to provide a visual readout of motor neuron activation. They confirmed that low SMN1 levels are associated with low neuronal influx of calcium ions, which play a critical role in triggering neurotransmitter release and thus stimulating the muscles. With their zebrafish model, Mr. See and Dr. Winkler also identified another gene with a similar effect, neurexin, which is important in synaptic structure but had never been implicated in SMA.

In a surprise discovery, the researchers found they could use the same sensor to see activation of a neighboring cell type called Schwann cells. "This gives us the unique opportunity to look at the role of SMN1 not just in motor neurons but also in the surrounding tissue," said Mr. See.

They saw reduced excitability in Schwann cells also, suggesting that a full understanding of SMA will require a broader view of the affected cell populations. Their results provide several new insights into the fundamental processes disrupted in SMA.

Acute T-cell Lymphoblastic Leukemia and Lymphoma (T-ALL/T-LBL)
Human acute T-cell lymphoblastic leukemias (ALL) and lymphomas (LBL) have high relapse rates in pediatric patients and high mortality rates in adults. Hui Feng, M.D., Ph.D., currently at the Pharmacology Department and Center for Cancer Research at Boston University School of Medicine, is using a zebrafish model of leukemia to search for promising targets for new molecular treatments for these diseases.

To date, studies have identified several biological pathways involved in ALL and LBL, all with a known oncogene in common called c-Myc. However, Myc is so common, involved in regulating more than 15 percent of all genes, that it is very hard to study.

"Because this is a huge list of downstream targets, it is very challenging to predict which genes in the pathway to target to treat Myc-related cancers," said Dr. Feng.

In work performed in collaboration with Thomas Look, M.D., at the Dana-Farber Cancer Institute, Dr. Feng is combining the power of zebrafish genetics with human clinical studies to hone in on potential genes of interest.

Using a fish strain that reliably develops T-cell lymphoma by two months of age, they identified a novel gene called DLST that is involved in metabolism and energy production in cells. Evidence from human cancer cell lines and patients indicate that abnormally high levels of the protein may be involved in the human disease as well.

Reducing DLST activity in the fish significantly delayed tumor progression and growth, suggesting it is a promising target for developing new therapies for ALL and LBL.

ABOUT THE INTERNATIONAL CONFERENCE ON ZEBRAFISH GENETICS AND DEVELOPMENT: The zebrafish emerged as a major model system in 1994 with the first international conference at Cold Spring Harbor with 350 participants. This year the zebrafish community celebrated its 10th biennial international conference with more than 900 participants in Madison, WI. Studies using the zebrafish as a model system have allowed us to understand the genetic control of early development that underlie many human diseases. For more information about the conference, see http://www.zebrafishgenetics.org/

ABOUT GSA: Founded in 1931, the Genetics Society of America (GSA) is the professional membership organization for scientific researchers, educators, bioengineers, bioinformaticians and others interested in the field of genetics. Its nearly 5,000 members work to advance knowledge in the basic mechanisms of inheritance, from the molecular to the population level. GSA is dedicated to promoting research in genetics and to facilitating communication among geneticists worldwide through its conferences, including the biennial conference on Model Organisms to Human Biology, an interdisciplinary meeting on current and cutting edge topics in genetics research, as well as annual and biennial meetings that focus on the genetics of particular organisms, including C. elegans, Drosophila, fungi, mice, yeast, and zebrafish. GSA publishes GENETICS, a leading journal in the field and an online, open-access journal, G3: Genes|Genomes|Genetics. For more information about GSA, please visit www.genetics-gsa.org. Also follow GSA on Facebook at facebook.com/GeneticsGSA and on Twitter @GeneticsGSA.

Phyllis Edelman | EurekAlert!
Further information:
http://www.genetics-gsa.org
http://www.zebrafishgenetics.org/

More articles from Life Sciences:

nachricht How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH

nachricht A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>