Wednesday 20 August, 2014

Zebrafish to give insight into causes and treatment of human diseases

Published On: Sat, Jul 7th, 2012 | Genomics | By BioNews

Researchers including one of Indian origin are now using Zebrafish, which are popular as aquarium fish, 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 (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, 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,” Thakur said.

The fish have a genetic mutation that disrupts de novo synthesis of an important signalling molecule called phosphatidylinositol (PI).

The lack of de novo PI synthesis, 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.

Yan Liu, a postdoctoral researcher working in Dr. Randall Peterson’s lab at the Massachusetts General Hospital, 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 tumour 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.

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.

The researchers used the zebrafish model to study diseases like Spinal Muscular Atrophy and cute T-cell Lymphoblastic Leukemia and Lymphoma also.

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