This research application focuses on repair of the injured spinal cord. Our experiments are based on the hypothesis that the cellular environment of the injured CNS limits the extent to which regrowth of damaged axons is initiated and maintained. Accordingly, the long-term objectives of this research program are to determine whether a more favorable milieu for regeneration can be established in the injured spinal cord and to gain a better understanding of the interaction between environmental factors and intrinsic neuronal growth properties.
The aims of this proposal are: (1) To determine whether immediate or delayed transplants of embryonic spinal cord tissue can restore anatomical continuity in the injured spinal cords of adult rats. Anterograde and retrograge neuroanatomical tracing techniques and immunocytochemistry will be used to map the extent of axonal connectivity between host and donor tissues. The regenerative responses of injured fibers of specific long tracts ot embryonic CNS tissue will be determined by light and electron microscopy. We will also investigate whether axonal connections between host and donor tissues can mediate any recovery of locomotor and reflex function. (2) To determine whether the glial environment of The CNS inhibits elongation of axons from neurons that have considerable inherent growth potential. Ventral root-dorsal root anastomoses will be performed to test the ability of adult motoneurons to regenerate through the PNS-CNS interface at the dorsal root entry zone. Whether neurons with neogenic growth properties can traverse the glial limiting membrane of the adult CNS will also be determined. (3) To resolve whether the distance over which fiber elongation occurs in the injured spinal cord is a function of available postsynaptic sites either rostral or caudal to the level of injury. Specifically, we will use grafts of peripheral nerve segments to test whether CNS fibers elongating through such grafts can continue to advance for long distances after re-entering a spinal cord segment that had been extensively denervated by serial dorsal rhizotomies or completely isolated by transections above and below the graft insertion site. Together, these investigations should provide a foundation of basic information for developing strategies for promoting axonal regeneration and functional recovery in the injured spinal cord.
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