In the United States alone, a new spinal cord injury occurs every 40 minutes and to date, there are no effective treatments to restore lost sensory and motor function resulting from injury. This is largely due to the lack of regenerative capacity of the mammalian central nervous system (CNS). Unlike mammals, Xenopus frogs are able to regenerate their spinal cord after injury as tadpoles, but lose this ability as adult frogs. The ability to regenerate the CNS declines as development progresses, a phenomenon that can be observed throughout the vertebrate subphylum. By using Xenopus as an experimental model for spinal cord injury, we have the opportunity to elucidate the molecular factors that promote and inhibit functional recovery after spinal cord injury by comparing the regeneration response of the tadpole to that of the adult frog. The body of literature encompassing the efforts of several decades of research suggests it is unlikely that an effective treatment for SCI will be found by the targeted deletion or addition of a single gene. As microRNAs (miRNAs) can simultaneously modulate the expression of hundreds of genes, we feel that they make excellent candidates to enhance functional recovery after SCI. In previous work, we found miR-133b to promote CNS regeneration. Our preliminary data shows miR-133b to be developmentally regulated in Xenopus, as it is robustly expressed in the tadpole CNS and is substantially reduced in the adult. In the research proposed herein, we will establish Xenopus laevis as a new model for spinal cord compression injury research and use Next-Generation sequencing to assay the changes in miRNA expression that occur during successful CNS regeneration in the tadpole, compared to failed regeneration in the adult frog. We will select candidate miRNAs that promote regeneration in tadpoles and express them in adult frogs in an effort to promote functional recovery in the adult. We will also inhibit the expression of these same miRNAs in developing embryos to confirm their contribution to spinal cord regeneration and determine their role in nervous system development. We expect the results of this research to generate new therapeutic targets to promote functional recovery from SCI in humans. The National Institutes of Health (NIH) is interested in providing undergraduate research opportunities (URO) to develop the nation's best and brightest aspiring scientists. Universities whose primary focus is education are not regular recipients of NIH funding, and therefore have fewer research opportunities for undergraduates interested in careers in science. The results of a survey of URO participants indicated that undergraduates were more interested in research careers and advanced degrees when provided UROs [1]. Thus, funding developmental biology research in educationally focused universities will expand the pool of future developmental scientists by training students who would otherwise not be provided such opportunities. The research proposed herein will help accomplish this goal by engaging undergraduates and providing UROs in developmental biology, while simultaneously strengthening the research environment in our university.
Xenopus frogs can regenerate their spinal cord as tadpoles, but lose the ability to do so after developing into adult frogs. microRNAs are small molecules that regulate the expression of many other genes during development in all vertebrates. This project will determine how developmental changes in microRNA expression affect the ability of Xenopus frogs to regenerate their spinal cords. In doing so, we hope to increase our understanding of the genetic regulation associated with recovery from spinal cord injury and generate new therapeutic targets to promote recovery in humans.
