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Bioinformatics researchers identify protein mechanisms behind limb regeneration

February 15, 2010

The most comprehensive study to date of the proteins in a species of salamander able to regrow appendages may provide important clues to how similar regeneration could be medically induced in humans who have experienced severe tissue damage.

Bioinformatics researchers from the IU School of Informatics and Computing at IUPUI collaborated with the IU Center for Regenerative Biology and Medicine and other colleagues to investigate more than 300 proteins in the amputated limbs of axolotls. Axolotls are a type of salamander with the unique natural ability to regenerate appendages. Researchers hope this knowledge will contribute to a better understanding of the mechanisms that allow limbs to regenerate. Their findings were published online in the journal Biomedical Central Biology on November 30 (BMC Biology 7:83, 2009).

Bioinformatics was essential to the study’s success. “Traditionally, biological research has focused on analyzing one or few proteins at a time. Bioinformatics allows us to look holistically at proteins that carry out the regeneration process,” said Mathew Palakal, Ph.D. and Director of the Text Information Mining, Analysis, Prediction Laboratory (TiMAP) within the IU School of Informatics and Computing. This research specifically examined the networks and relationships between identified proteins. “We analyzed the patterns of expression in proteins present during regeneration – how they differ at various points in the process,” said Deepali Jhamb, a Ph.D. candidate in Bioinformatics and co-author of the study. “We were then able to determine functional clusters in the data that are critical to limb regrowth.” Future research will utilize additional systems biology tools to develop a global protein map of limb regeneration.

With few exceptions – notably the antlers of moose, deer and their close relatives, the tips of the fingers and toes of humans and rodents, and the ear tissue of certain strains of mice and rabbits – the appendages of mammals do not regenerate after amputation. Limb regeneration in the axolotl occurs when undifferentiated cells accumulate under the wound epidermis at the amputation site, a process known as the establishment of a blastema. These cells are derived by the reprogramming of differentiated cells to a less specialized state, and from resident stem cells.

Investigating the proteins found in the axolotl limb, the researchers noted three findings that appear to have significance in reprogramming cells to grow new limbs: 1.) Quantities of enzymes involved in metabolism decreased significantly during the regeneration process; 2.) There were many critical proteins that helped prevent cell death after traumatic amputation; 3.) A protein that appears to keep cells from dividing until they are fully dedifferentiated and reprogrammed to form a new limb was expressed at high levels throughout blastema formation.

Co-authors of the study, which was funded by the W. M. Keck Foundation, are David L. Stocum, Ph.D., Nandini Rao, Ph.D. and graduate student Behnaz Saranjami of the School of Science; Fengyu Song, D.D.S., M.S., Ph.D. of the IU School of Dentistry; Mu Wang, Ph.D. and Michael W. King, Ph.D. of the IU School of Medicine; Bingbing Li, Ph.D. of Central Michigan University; S. Randal Voss, Ph.D. of the University of Kentucky; and Derek J. Milner, Holly L. D. Nye and Jo Ann Cameron, Ph.D. of the University of Illinois. All except the final four are also affiliated with the IU Center for Regenerative Biology and Medicine, of which David L. Stocum, Ph.D. is director.

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