This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Most victims of spinal cord injury (SCI) are in the prime of their life and often require costly supportive care for many decades. In SCI involving the dorsal white matter, the centrally projecting axons of the dorsal root ganglion (DRG) are severed. Finding ways to stimulate regeneration of these fibers and formation of functional synaptic contacts is crucial for the restoration of sensory perception from the trunk and limbs. Recent studies have identified a novel, neurite growth promoting function of the enzyme acetylcholinesterase (AChE) which is until recently well known only for its catalytic function at cholinergic synapses. It is present in neurons of DRG though there are no synapses in DRG. Further, in vitro studies of DRG neurons show that AChE promotes neurite growth in DRG neurons. Based on these findings and preliminary results, the long term goal of this research is to investigate AChE's role as a neurite growth factor and its potential use to stimulate regeneration of the central processes of DRG in SCI. Using primary cultures of DRG neurons of rat and purified ACHE, employing techniques of cell and molecular biology, the experiments in specific aims of this proposal are designed to test the following hypotheses:
Specific Aim 1. AChE's effect on neurite growth in DRG neurons is independent of its catalytic function.
Specific Aim 2. AChE's effect on neurite growth is mediated by its carbohydrate moiety.
Specific Aim 3. AChE binds to neurons and this binding is necessary for AChE-induced neurite growth.
Specific Aim 4. AChE alters the expression profiles of genes which regulate neurite outgrowth. Results from these studies will identify the neurotrophic site of AChE and help decipher the underlying mechanisms including AChE-dependent changes in expression profiles of genes regulating neurite growth. These results will help in developing strategies using AChE or a short peptide functional analogue of AChE to promote neurite growth and thus accelerate functional recovery following SCI.
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