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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD038679-11
Application #
7802312
Study Section
Special Emphasis Panel (ZRG1-RUS-B (06))
Program Officer
Parrott, Estella C
Project Start
2000-04-05
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2013-03-31
Support Year
11
Fiscal Year
2010
Total Cost
$280,086
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Gill, Bradley C; Lin, Dan Li; Balog, Brian M et al. (2016) Molecular Assessment of Neuroregenerative Response in the Pudendal Nerve: A Useful Tool in Regenerative Urology. SDRP J Biomed Eng 1:
Song, Qi-Xiang; Balog, Brian M; Kerns, James et al. (2015) Long-term effects of simulated childbirth injury on function and innervation of the urethra. Neurourol Urodyn 34:381-6
Cruz, Yolanda; Pastelín, César; Balog, Brian M et al. (2014) Somatomotor and sensory urethral control of micturition in female rats. Am J Physiol Renal Physiol 307:F1207-14
Jiang, Hai-Hong; Gill, Bradley C; Dissaranan, Charuspong et al. (2013) Effects of acute selective pudendal nerve electrical stimulation after simulated childbirth injury. Am J Physiol Renal Physiol 304:F239-47
Lenis, Andrew T; Kuang, Mei; Woo, Lynn L et al. (2013) Impact of parturition on chemokine homing factor expression in the vaginal distention model of stress urinary incontinence. J Urol 189:1588-94
Gill, Bradley C; Balog, Brian M; Dissaranan, Charuspong et al. (2013) Neurotrophin therapy improves recovery of the neuromuscular continence mechanism following simulated birth injury in rats. Neurourol Urodyn 32:82-7
Gill, Bradley C; Damaser, Margot S; Vasavada, Sandip P et al. (2013) Stress incontinence in the era of regenerative medicine: reviewing the importance of the pudendal nerve. J Urol 190:22-8
Pastelin, C F; Juarez, R; Damaser, M S et al. (2012) Neural pathways of somatic and visceral reflexes of the external urethral sphincter in female rats. J Comp Neurol 520:3120-34
Jiang, Hai-Hong; Salcedo, Levilester B; Damaser, Margot S (2011) Quantification of neurological and other contributors to continence in female rats. Brain Res 1382:198-205
Jiang, Hai-Hong; Damaser, Margot S (2011) Animal models of stress urinary incontinence. Handb Exp Pharmacol :45-67

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