Project 3 of our Program Project is entitled """"""""lon Channels in Afferent Sensitization and Detrusor Overactivity"""""""" (Project Director: Naoki Yoshimura, Department of Urology). The following key aims will utilize unique and innovative expertise, available in our institutions, to understand the pathophysiology of detrusor overactivity (DO) and detrusor sphincter dyssynergia (DSD), especially by targeting afferent hyperexcitability, which has been proposed as one of the important mechanisms underiying lower unnary tract dysfunction in chronic spinal cord injury (SCI). First, we will study the correlated changes in bladder activity (i.e., DO) and the expression and functional properties of K""""""""^ ion channels after SCI as we have previously found that altered expression of voltage-gated K* channels is one of the key events for the induction of C-fiber hyperexcitability resulting in bladder overactivity. Secondly, we will investigate changes in the K^ and Ca^* ion channel mechanisms in pudendal afferent pathways innervating the urethra containing external urethral sphincter (EUS), and their correlation with urethral hyperactivity (i.e., DSD) after SCI as there are no previous studies that examined the SCI-induced changes in functional properties of pudendal afferent neurons innervating the urethra. Lastly, we will investigate the roles of nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) and p38 MAPK signaling in neuroplasticity of bladder and urethral afferent pathways that underlies SCI-induced DO and DSD. We will also utilize the small-interfenng RNA technique to identify molecular correlates in K* ion channel subunits that induce bladder and urethral afferent hyperexcitability. The long-term objectives of the research program are to establish new and effective therapeutic targets and/or interventions strategies for the treatment of urological problems in spinal cord disorders. There is significant synergy especially with Projects 1 and 4, which will respectively examine peripheral afferent remodeling and spinal mechanisms controlling EUS function. Project 3 also maximizes the uses of the resources of Animal and Optical Imaging Cores.

Public Health Relevance

Following spinal cord injury, increased excitability of bladder and urethral afferents lead to overactivity. Determining the ion channel mechanisms involved and preventing changes in their expression by anti-growth factor treatment could lead to a new method to prevent/treat LUT dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK093424-02
Application #
8723175
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Tyagi, Pradeep; Kashyap, Mahendra; Yoshimura, Naoki et al. (2016) Past, Present, and Future of Chemodenervation With Botulinum Toxin in the Treatment of OAB. J Urol :
Kadekawa, Katsumi; Yoshimura, Naoki; Majima, Tsuyoshi et al. (2016) Characterization of bladder and external urethral activity in mice with or without spinal cord injury--a comparison study with rats. Am J Physiol Regul Integr Comp Physiol 310:R752-8
Tyagi, Pradeep; Kadekawa, Katsumi; Kashyap, Mahendra et al. (2016) Spontaneous Recovery of Reflex Voiding Following Spinal Cord Injury Mediated by Anti-inflammatory and Neuroprotective Factors. Urology 88:57-65
Yu, Yongbei; Daugherty, Stephanie L; de Groat, William C (2016) Effects of nicotinic receptor agonists on bladder afferent nerve activity in an in vitro bladder-pelvic nerve preparation. Brain Res 1637:91-101
Kashyap, Mahendra; Pore, Subrata; Yoshimura, Naoki et al. (2016) Constitutive expression Of NGF And P75(NTR) affected by bladder distension and NGF antisense treatment. Life Sci 148:93-8
Walker, K A; Ikeda, Y; Zabbarova, I et al. (2015) Fgfr2 is integral for bladder mesenchyme patterning and function. Am J Physiol Renal Physiol 308:F888-98
Sunagawa, Masataka; Wolf-Johnston, Amanda; Nomiya, Masanori et al. (2015) Urinary bladder mucosal responses to ischemia. World J Urol 33:275-80
Sugino, Yoshio; O'Malley, Katherine J; Wang, Zhou et al. (2015) Laser-capture microdissection for analysis of cell type-specific gene expression of muscarinic receptor subtypes in the rat bladder with cyclophosphamide-induced cystitis. Int Urol Nephrol 47:637-42
Ogawa, Teruyuki; Ishizuka, Osamu; Ueda, Tomohiro et al. (2015) Current and emerging drugs for interstitial cystitis/bladder pain syndrome (IC/BPS). Expert Opin Emerg Drugs 20:555-70
Yoshikawa, S; Kawamorita, N; Oguchi, T et al. (2015) Pelvic organ cross-sensitization to enhance bladder and urethral pain behaviors in rats with experimental colitis. Neuroscience 284:422-9

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