Despite pervasive evidence of the negative impact overactive bladder (OAB) ensues upon individual health; it remains a widespread medical problem in the United States (US) for which there is no cure or effective long- term treatment. OAB is characterized by lower urinary tract symptoms (LUTS), most notably the sudden and frequent urge to urinate. An estimated ~16.5% of the population is affected by OAB; however, this underscores the prevalence of OAB as the number of affected individuals who actually seek medical care is as little as 25% due to fear of embarrassment and shame. The principle treatment for OAB relies upon antimuscarinics. However, patient discontinuation rates of 80-90% within the first year of treatment attests to the lack of effective symptomatic control and adverse effects associated with such therapeutics. Normal bladder function represents the voluntary control of urine voiding and storage, a process predominately regulated by the coordinated contraction and relaxation of urinary bladder smooth muscle (UBSM). Spontaneous action potentials within UBSM cells underlie the phasic contractile activity of the bladder. Thus, under pathologic conditions such as OAB, the bladder is subject to recurrent and involuntary contractions. These observations have directed our attention towards potassium (K+) ion channels, which fundamentally regulate the shape, duration, and frequency of action potentials. Among K+ ion channels, preliminary data from our laboratory has demonstrated that members of the voltage-gated (KCNQ) channel family are functionally expressed in human UBSM. These findings are noteworthy because of the five currently known KCNQ channels (KCNQ1-5), there is strong evidence indicating their activity and function is both subtype- and tissue- specific. In addition, the therapeutic potential of KCNQ channels is evidenced by the recently approved antiepileptic drug known as retigabine, shown to have beneficial bladder effects. Therefore, the long-term objective of this fellowship training proposal will utilize two experimental aims to test the hypothesis that KCNQ channels are critical regulators of human UBSM excitation-contraction coupling and thus KCNQ channels provide a novel target for the pharmacological treatment of OAB.
Aim 1 will determine the expression and localization of KCNQ channel subtypes in human UBSM and the specific subunit compositions native to this tissue.
Aim 2 will elucidate the functional role of KCNQ channel subtypes in human UBSM excitability and contractility by examining channel activity using pharmacological modulators. We have developed a comprehensive fellowship training plan utilizing techniques in molecular biology, isometric tension recordings, live-cell Ca2+ imaging, and perforated patch-clamp electrophysiology. As this fellowship proposal uses human UBSM from donor patients on a regular basis, these studies are highly translational. The sponsors overseeing this training include Dr. Petkov, a world-renowned leader in ion channel research and Dr. Rovner, a clinical urologist and internationally-recognized expert in the field of lower urinary tract dysfunction and OAB.
Overactive bladder (OAB) is a significant medical problem in the United States and worldwide that lacks both a cure and effective long-term treatment strategy. Poised as key regulators of urinary bladder smooth muscle (UBSM) function, this fellowship training proposal aims to elucidate the role of voltage-gated KCNQ channels in human UBSM and to validate their potential as pharmacological targets for OAB. With expert fellowship sponsors from both the fields of ion channel research and clinical urology, this fellowship training plan is well poised for success.
|Provence, Aaron; Rovner, Eric S; Petkov, Georgi V (2017) Regulation of transient receptor potential melastatin 4 channel by sarcoplasmic reticulum inositol trisphosphate receptors: Role in human detrusor smooth muscle function. Channels (Austin) 11:459-466|
|Hristov, Kiril L; Parajuli, Shankar P; Provence, Aaron et al. (2016) Testosterone decreases urinary bladder smooth muscle excitability via novel signaling mechanism involving direct activation of the BK channels. Am J Physiol Renal Physiol 311:F1253-F1259|
|Provence, Aaron; Malysz, John; Petkov, Georgi V (2015) The Novel KV7.2/KV7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility. J Pharmacol Exp Ther 354:290-301|
|Provence, Aaron; Hristov, Kiril L; Parajuli, Shankar P et al. (2015) Regulation of Guinea Pig Detrusor Smooth Muscle Excitability by 17?-Estradiol: The Role of the Large Conductance Voltage- and Ca2+-Activated K+ Channels. PLoS One 10:e0141950|