The animal studies in this renewal application will parallel the clinical trial studies to further understand the mechanisms of somatic reinnervation for restoration of bladder emptying function.
Aim 1 : Address the following questions: ? Will administration of growth factors into the reinnervated urinary bladder wall improve recovery? ? Which are the most effective growth factors to use? Will it be: a) Factors produced by the decentralized bladder cells (smooth muscle, intramural ganglia, interstitial, urothelial cells), b) Factors that promote neonatal survival of bladder spinal motoneurons; or, c) Factors that optimally attract the somatic motor fibers from the donor obturator nerve? ? What growth factors promote functionally optimal afferent reinnervation? Aim 2: Address the following questions: ? Is the one anterior vesical branch of the pelvic nerve on each side that is reinnervated by a portion of the obturator nerve branch sufficient to achieve effective bladder emptying and sensation? ? Is the loss of innervation from transecting vesical branches alone enough to result in loss of bladder function or this there sufficiently retained innervation through other branches such that the voiding function recovers with time? ? Is the recovery of voiding behavior truly the result of the new neural pathway from the nerve transfer or some other spontaneous recovery? ? Will obturator to anterior branch of the pelvic nerve transfer performed before decentralization improve recovery of bladder function? Aim 3: Answer the following questions using the canine tissue bank accrued from the previous funding cycles and from the new animals in these proposed studies: ? What properties have changed in the axotomized motor nerves and how are these altered by rerouting? ? What types of efferent fibers are reinnervating the bladder from the obturator nerve and on what type of cells do these new fibers terminate? ? Do the new bladder efferent fibers originate from the ventral horn, sympathetic chain ganglia or both? ? What types of afferent fibers are growing into the bladder from the obturator nerve and what are their en- organ targets? Is it urothelium, intramural ganglia, muscles, or blood vessels?
Because of our success with peripheral nerve transfer for restoration of function in preclinical animal investigations, we plan to begin human clinical translation very cautiously with a patient population that most closely matches our preclinical canine model which are patients that have lost control of their bladder, bowel and sexual function but retain intact ambulation recruited primarily from patients with sacral chordoma following tumor removal with sacrectomy surgery. The animal studies in this renewal application will parallel the clinical trial studies to further understand the mechanisms of somatic reinnervation for restoration of bladder emptying function. At present there are no satisfactory interventions for patients with an atonic neurogenic bladder that have lost their peripheral parasympathetic nerves to the bladder and restoration of bladder emptying function is expected to greatly improve the quality of life of these patients.
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