Molecular Determinants Fundamental to Axon Regeneration after SCI.

摘要

There are no therapies available that restore motor impairments resulting from spinal cord injury (SCI). Soldiers with SCI are permanently paralyzed and in need of lifelong care. Promoting axon regeneration after SCI may lead to the formation of axon circuits that may be involved in (or recruited for) motor functions. In the mammalian spinal cord, axon regeneration is frustrated by inhibitors such as chondroitin sulfate proteoglycans (CSPGs) expressed by reactive astrocytes present at the injury site. In adult zebrafish, Danio rerio, some brainstem neuronsare able to grow their axon beyond a spinal cord injury, even though inhibitory CSPGs are present. Based on these findings we have developed an overall working hypothesis that the ability to grow an axon over CSPGs is intrinsic to the zebrafish brainstem neurons and entails the expression of a distinct set of genes. In Phase 3, we propose to employ an in vitro model system to determine the relationship between L1.1 and the CSPG neurocan, on axon growth from primary brainstem neurons from adult zebrafish (Specific Aim 1). We also will examine in vivo the role of PTP in inhibition of axon regeneration (Specific Aim 2). In addition, we propose to determine the effects of identified transgenic over expressing genes crucial for axon regeneration (Specific Aim 3). The results of the proposed experiments will provide information that may serve as the basis for the development of tailored strategies to promote axon regeneration across injury sites in the spinal cord.