Urinary incontinence is a major health care problem in the United States and an area of high priority for NIDDK. This DK55387 competitive renewal grant will explore several new developments using muscle derived stem cells (MDSC) as a treatment of stress urinary incontinence. We were extremely productive during the initial ROl grant funding period and we would like to thank NIDDK for their support. All key objectives of the previous grant were successfully completed. This resulted in 7 peer review papers, 3 more manuscripts are in press and 3 are near completion and will be submitted. Our findings were publicized at 16 international meetings and through 24 submitted abstracts. As a result of our work, we won 3 international contests and submitted 3 patents. A NTDDK Ki 2 Physician Scientist fellow, 3 PhDs. 2 Ph.D. candidates and 3 medical students entering urology worked on our project. Among them are 3 women (1 African American) and 2 African American men. What questions have been left unresolved? The experiments during the present grant identified new issues. We have evidence that bladder injection of MDSC rather than myoblasts persist in the bladder up to 6 months. MDSC can differentiate into smooth muscle. Most importantly, MDSC were able to improve the contractility of damaged bladder muscle while myoblasts were not. In the renewal grant, we want to investigate several important issues, such as: 1. Will MDSC injection improve function in a damaged urethral sphincter? 2. What is the potential for MDSC to differentiate into neurons and improve urologic function? 3. If MDSC becomes neurons, what neurons do they become, afferent, sympathetic, and/or parasympathetic? 4. Do MDSC become neurons in normal conditions or under conditions of acute or chronic stress and neuropathy? The Key Aims of this grant include: 1. Evaluation of the long-term safety and persistence of allogenic MDSC versus myoblasts urethral injection, 2. Measure urethral MDSC injection to improve sphincter function by assessing leak point pressure (LPP) and urethral strip contractility, 3. Assessment of MDSC ability to improve peripheral nerve functions and differentiate into neurons, and 4. Isolation, purification, and proliferation of human MDSC that would be suitable for clinical trial. We want to strongly emphasize that our stem cell research is in complete compliance with the federal guideline on embryonic stem cell research. We want to underscore that these stem cells have not been obtained from embryos (animal or human) or cell lines of embryonic stem cells.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-UROL (01))
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Kusek, John W
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University of Pittsburgh
Schools of Medicine
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Kitta, Takeya; Yoshikawa, Satoru; Kawamorita, Naoki et al. (2016) The effect of ovariectomy on urethral continence mechanisms during sneeze reflex in middle-aged versus young adult rats. Neurourol Urodyn 35:122-7
Kawamorita, Naoki; Kaiho, Yasuhiro; Miyazato, Minoru et al. (2015) Roles of the spinal glutamatergic pathway activated through ?-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and its interactions with spinal noradrenergic and serotonergic pathways in the rat urethral continence mechanisms. Neurourol Urodyn 34:475-81
Sumino, Yasuhiro; Yoshikawa, Satoru; Mimata, Hiromitsu et al. (2014) Therapeutic effects of IGF-1 on stress urinary incontinence in rats with simulated childbirth trauma. J Urol 191:529-38
Koike, Yusuke; Furuta, Akira; Suzuki, Yasuyuki et al. (2013) Pathophysiology of urinary incontinence in murine models. Int J Urol 20:64-71
Yoshimura, Naoki; Miyazato, Minoru (2012) Neurophysiology and therapeutic receptor targets for stress urinary incontinence. Int J Urol 19:524-37
Kitta, Takeya; Haworth-Ward, Donna J; Miyazato, Minoru et al. (2011) Effects of ovariectomy and estrogen replacement on the urethral continence reflex during sneezing in rats. J Urol 186:1517-23
Furuta, Akira; Suzuki, Yasuyuki; Asano, Koji et al. (2011) Urethral compensatory mechanisms to maintain urinary continence after pudendal nerve injury in female rats. Int Urogynecol J 22:963-70
Kitta, Takeya; Miyazato, Minoru; Chancellor, Michael B et al. (2010) Alpha2-adrenoceptor blockade potentiates the effect of duloxetine on sneeze induced urethral continence reflex in rats. J Urol 184:762-8
Smaldone, M C; Chen, M L; Chancellor, M B (2009) Stem cell therapy for urethral sphincter regeneration. Minerva Urol Nefrol 61:27-40
Furuta, Akira; Asano, Koji; Egawa, Shin et al. (2009) Role of alpha2-adrenoceptors and glutamate mechanisms in the external urethral sphincter continence reflex in rats. J Urol 181:1467-73

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