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 Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute

nachricht Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>