Prerequisite for normal storage and voiding
functions of the urinary bladder is a coordinated
interaction between the muscle components of the
bladder wall (detrusor) and its outlet (urethra and
sphincter). Lower urinary tract dysfunction can be
caused by bladder outlet obstruction and
neurological diseases including spinal cord injury
and multiple sclerosis. Detrusor (bladder muscle)
overactivity (DO) often constitutes a part of an
overactive bladder syndrome, greatly reducing the
patients’ quality of life. High pressure DO after
SCI can irreversibly damage the kidneys. New
therapies preventing the causes of overactive
bladder are urgently needed.
Previously we showed that prolonged treatment with inosine leads to a significant improvement in bladder function after SCI. We showed that poly(ADP-ribose) polymerase 1 (PARP-1) signaling was increased in the neurogenic bladder and reduced after treatment with inosine. Here we will investigate how the activation of PARP-1 signaling leads to DO, and test the effects of inosine and pharmaceutic PARP-1 inhibition on the bladder function. Using the animal models of SCI and MS and human patients’ material, we will analyze PARP-1 molecular signature in dysfunctional bladders. We will apply state of the art methods in molecular biology to discover the activated processes in the neurogenic bladder and the effects of inhibitors / drugs. This will allow us to study the cross-talk between PARP-1 and immune cell activation, and identify the specific cell types contributing to detrimental bladder remodeling. Interrupting this link will allow novel therapeutic approaches, aiming at removing the cause of DO rather than simply ameliorating symptoms.