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 Bare bones: Making bones transparent
27.04.2017 | California Institute of Technology

nachricht Link Discovered between Immune System, Brain Structure and Memory
26.04.2017 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

Bare bones: Making bones transparent

27.04.2017 | Life Sciences

Study offers new theoretical approach to describing non-equilibrium phase transitions

27.04.2017 | Physics and Astronomy

From volcano's slope, NASA instrument looks sky high and to the future

27.04.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>