A major disability following spinal cord injury (SCI) is urinary dysfunction due to the disconnection of supraspinal inputs and the lack of coordinated activities that develop after injury between the bladder and the external urethral sphincter (EUS). While much work in bladder recovery following SCI has focused on pharmacological intervention and/or functional electrical stimulation of the bladder or peripheral nerves, relativey few studies have focused on central neuronal regeneration for the recovery of efficient micturition especially in chronic SCI, which is the condition of most SCI patients. In addition, there is very little basic biological information concerning the fundamental capacity of chronicall injured axons to regenerate. Recently, we have developed a strategy using the classic technique of peripheral nerve auto-grafting (PNG) with the critical addition of acidic fibroblast growth factor (?FGF) + chondroitinase ABC (ChABC) to improve growth across the PNG/host spinal cord interface. Even after complete cord transection in adult rats, this strategy can allow for remarkably long distance regeneration of a portion of axons from several of the critical descending brainstem systems that control urination. The regeneration is exceedingly slow. Unlike acute SCI, in the chronic state there is already formation of dense glial scarring and axonal dystrophy and entrapment within the lesion. To maximize the regeneration capacity of chronically injured axons and functional outcomes, our goal is to enhance PNG+?FGF+ChABC treatment by a novel technique that can more persistently reduce or overcome the effect of inhibitory molecules and robustly increase intrinsic growth machinery. There are 4 specific aims that will be addressed.
Aim 1 will test the hypothesis that PNG+?FGF+ChABC can enhance nerve regeneration, improve the PNG/cord interface, and slowly promote functional bladder recovery in rats with chronic T8 contusive SCI (2 months) more efficiently than the various components of the therapy used alone.
Aim 2 will test the hypothesis that the combination of PNG+?FGF+ChABC with systemic delivery of intracellular sigma peptide (ISP) application can enhance nerve regeneration and promote more rapid or complete functional bladder recovery in rats with chronic T8 contusive SCI (2 months) more efficiently than the individual components of the therapy used alone.
Aim 3 will test the hypothesis that the combination of PNG+?FGF+ChABC with suppressor of cytokine signaling-3 (SOCS3) short hairpin RNA application can enhance nerve regeneration and promote functional bladder recovery in rats with chronic T8 contusive SCI (2 months) more efficiently than the individual parts of the therapy used alone.
Aim 4 will test the hypothesis that the combination of PNG+?FGF+ChABC with ISP/SOCS3 shRNA application can maximally enhance nerve regeneration and promote functional bladder recovery in rats with chronic T8 contusive SCI (2 months). The accomplishments and advances obtained via this multipartite strategy have the potential to lead to an unprecedented amount of functional plasticity/regeneration and bladder recovery after chronically contusive SCI.
Recently, significant accomplishments have been made in the development of new strategies to promote regeneration and functional recovery after spinal cord injury (SCI). The focus of most labs has been on acute injury and walking function. There are very few studies to develop strategies to promote nerve regeneration to restore bladder control after chronic SCI, which is a major unmet goal. This proposal addresses an important problem, bladder dysfunction in a chronically contusive SCI model that simulates the condition of most patients with SCI. The ultimate goal is to promote enhanced regeneration/sprouting from brainstem neurons that control urination. The hypothesis that we will test is that by using a non-invasive delivery of a novel peptide, intracellular sigma peptide, or genetic short hairpin RNA manipulations to down regulate gene suppressor of cytokine signaling-3 in combination with a bridging strategy could lead to a more rapid or better recovery of bladder function after chronically contusive SCI. Success in this phase of the project would lay the groundwork for a potential therapeutic strategy for chronic SCI patients to restore bladder control and improve the quality of life of SCI patients.
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