Biomarkers predicting the severity of obstruction-induced bladder dysfunction

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DESCRIPTION (provided by applicant): Bladder dysfunction secondary to benign prostatic hyperplasia (BPH) is a major affliction of aging men. BPH can initiate changes associated with lower urinary tract symptoms (LUTS). Although these symptoms are related to the effects of an enlarging prostate there appears to be no direct relationship between prostate size and severity of obstructive bladder symptoms. Therefore, urodynamic findings cannot accurately predict either level of bladder pathology, or potential for recovery following surgery or pharmacological therapy. Thus, bio-markers that can identify the severity of male obstructive bladder dysfunction, and at what point the dysfunction becomes irreversible, would be of significant value in the management of the disorder. Although there is considerable evidence that partial outlet obstruction results in both ischemic and free radical damage to specific cellular and subcellular processes, especially cholinergic neurotransmission, and mitochondrial function, the exact characteristics of the membrane damage that mediates these cellular dysfunctions are not known, and are the bases for our proposed continuing studies. The hypothesis for our proposed study is: The progression of obstructive bladder dysfunction from compensated bladder function through irreversible bladder decompensation is mediated primarily by two processes: 1) Cellular and subcellular damage induced by ischemia/reperfusion, which can be characterized by progressively increasing oxidation, peroxidation, and nitration of specific cellular and subcellular membranes, especially those of the cholinergic nerves, synapses, and neuronal and cellular mitochondria, and 2) progressive replacement of functional smooth muscle with connective tissue. The specific aims of our proposal are: 1) Using our rabbit model of partial outlet obstruction, we will: a) quantitate the level of ROS and RNS damage to specific cellular and subcellular membranes; b) quantitate the Sm/C. We will determine how the levels of ROS and RNS damage to specific membrane systems correlate with the level of decompensation at each duration of obstruction; and also determine the Sm/C for each level of decompensation at each duration of obstruction. The cellular and subcellular membranes to be studied include: nuclei, cell wall, mitochondria, sarcoplasmic reticulum, nerve and synaptic membranes. 2) We will quantitate the degree of functional (contractile), structural (SM/C), and biochemical (ROS and RNS damage) recovery of obstructed bladders by removal of the partial outlet obstruction at increasing durations of obstruction. At each time point we will determine the level of bladder decompensation at both the time of reversal, and at the end of the recovery period. By directly comparing the structural and biochemical state of the bladder at the time of reversal with the structural and biochemical state of the bladder at the end of the recovery period we can determine the degree of structural and biochemical recovery; and by directly comparing these data with the functional recovery (or lack of recovery) of the bladder we will be able to identify specific mechanisms by which the bladder recovers from obstructive dysfunction; and the mechanisms involved in the bladder progressing to full decompensation. From these studies we expect to identify the characteristics of obstructed bladders that prevent the bladder from recovering even when the obstruction is removed. Through these studies we will generate significant new information related to our hypothesis. In addition, the data generated can be used to develop novel and specific and effective anti-oxidant products for the treatment of obstructive bladder dysfunction.