Center for Regenerative Biology and Medicine at Mount Desert Island Biological Laboratory.

摘要

The inability to regrow functional limbs or limb segments lost to trauma or disease is a significant biomedical problem, with substantial associated monetary and quality-of-life implications for the nearly two million affected U. S. citizens and active service members. Development of in vivo therapies that restore regenerative capacity first requires an understanding of the basic gene regulatory networks controlling this biology. Thus, characterizing ancestral regulatory circuitry controlling regeneration is a necessary and direct route to identifying the mechanistic causes of regenerative failure in mammals. This proposal offers unique promise in guiding the targeted development of in vivo therapies to restore/augment human limb regeneration. We will leverage our recent discovery that regenerative ability is widespread in basal vertebrates to conduct the first comparative analysis of appendage regeneration that incorporates model systems from all major groups of limbed vertebrates- cartilaginous fishes, ray-finned fishes, and tetrapods. Our unique approach will identify novel functional requirements for genes/gene networks in regulating appendage regeneration by marrying a comparative organismal approach with state-of-the-art systems-level analyses of gene expression using next generation RNA sequencing and functional analysis of candidate regulators in the genetically tractable zebrafish model system through in vivo disruption of gene function.