Clinically, during vaginal delivery of children, the tissues, muscles, and organs of the pelvic floor are compressed and injured. This includes the external urethral sphincter (EDS), the skeletal muscle of the urethra, which can become hypoxic during vaginal distension. In addition, the proximal pudendal nerve, which innervates the EUS, can be injured during vaginal childbirth and may not fully regenerate. These two injuries, along with other pelvic floor injuries, are strongly correlated with later development of stress urinary incontinence (SUI). Therefore, the mechanisms of incontinence development after vaginal delivery are multifactorial and may include incomplete pudendal nerve regeneration. Brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) are upregulated to facilitate nerve regeneration after injury but are downregulated for neuromuscular junction (NMJ) reformation after muscle injury. Therefore, muscle injury, such as during vaginal distension, may inhibit neuroregeneration from a simultaneous nerve injury. The hypothesis to be tested in the proposed project is that vaginal distension causes ischemic damage to the organs responsible for continence, including the EUS, which impedes the neuroregenerative response of the injured pudendal nerve by reduced neurotrophin synthesis and results in delayed neural and functional recovery. In the initial grant period, we developed & characterized a rat model of vaginal distension. We have also developed & characterized an independent rat model of proximal pudendal nerve injury.
Aim 1 of the proposed project is to determine the time course and extent of changes in local blood flow, tissue hypoxia, NMJs, and BDNF, NT-4, and trkB (the receptor for both BDNF and NT-4) expression in the genitourinary organs due to vaginal distensions of different extents and durations.
In aim 2 we will use an isolated cremaster muscle model to confirm ischemia & hypoxia and determine the effects of muscle ischemia on the same outcomes as in the experiments of aim 1. Dr. Siemienow, the co-Investigator, has extensive experience with this model of direct ischemic muscle injury.
In aim 3, we will determine the effects of target muscle injury of different extents and durations simultaneous with nerve injury on NMJs, nerve regenerative response, functional recovery, and BDNF, NT-4, and trkB expression, in both the vaginal distension and cremaster muscle models.
Aim 4 is to determine the effects of neurotrophin treatment as well as treatment with a neurotrophin antagonist on the same outcomes as in the experiments of aim 3 in both the vaginal distension and cremaster muscle models. The long term goals of this research program include investigation of the mechanism of incontinence development after vaginal delivery with the eventual goal of developing and testing novel treatments and potential prevention mechanisms for SUI. ? ? ?
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