Keith Sabin

Department

Genetics, Cell Biology, and Development (GCD)

Program

Molecular, Cellular, Developmental Biology and Genetics (MCDB&G)

Mentor

Karen Echeverri, PhD

Project description

Spinal cord injury (SCI) affects millions of people and is commonly associated with traumatic events like automobile accidents. Mammalian spinal cord injury leads to extensive scarring, neuronal cell death and axon degeneration causing loss of sensory and motor function below the injury site. One approach to treating SCI is to utilize neural stem cell (NSC) transplantation to regenerate lost neurons and severed axon tracts to reestablish sensory and motor function. However, utilizing mammalian models of SCI to develop NSC replacement therapeutic strategies aimed at reestablishing those lost connections has proved challenging. Remarkably, other vertebrates, such as the Mexican axolotl salamander, have retained the ability to functionally regenerate damaged nervous tissue after injury. We know that after injury NSCs contribute to functional spinal cord regeneration by 1) providing guidance cues to promote axon regeneration and 2) differentiate into new neurons. However, the molecular signals required that promote these processes are not well understood. Previous work in our lab used transcriptional profiling to identify genes that are differentially regulated during spinal cord regeneration. This approach identified key axon guidance molecules, such as Eph/Ephrin, Slit and semaphorin, which are differentially regulated during spinal cord regeneration. To determine the role of these molecules in regulating axon regeneration, I will use pharmacologic and genetic approaches to modulate the activity/expression of these molecules in NSCs after injury and assay for subsequent axon regeneration. Additionally, the extent to which NSCs differentiate into neurons that precisely integrate into regenerated neural circuits to restore sensory and motor function is not known. To address this knowledge gap, I will genetically label NSCs by electroporation of a plasmid where the Nestin promoter drives expression of GFP and I will track the NSC response to injury in real time using live cell in vivo fluorescent microscopy. My results will provide insight into the molecular pathways required to promote repair of damaged neural circuits leading to functional spinal cord regeneration.

Publications

Sabin and Kikyo. “Microvessicles as mediators of tissue regeneration.” Transl. Res. (2014) Apr;163(4):286-95. PMID: 24231336

Sabin K, Santos-Ferreira T, Essig J, Rudasill S and Echeverri K. “Dynamic membrane depolarization is an early regulator of ependymoglial cell response to spinal cord injury in the axolotl.” Submitted Dev. Bio.