Project 1. Neural mechanisms of pelvic organ cross-sensitization and chronic pelvic pain
Chronic pelvic pain is a major symptom of many complex clinical conditions, including
painful bladder syndrome (PBS), non-bacterial chronic prostatitis, irritable bowel syndrome
(IBS), vulvodynia. Pelvic organ cross-sensitization is considered to be one of the factors
contributing to chronic pelvic pain of unidentified origin. Cross-sensitization in the pelvis implies
the transmission of noxious stimuli from a diseased pelvic organ to an adjacent normal structure
resulting in the occurrence of functional (rarely structural) changes in the latter. Distribution of
sensitization in the pelvis mainly occurs via shared sensory neural pathways at prespinal, spinal
and supraspinal levels (reviewed in Malykhina A.P. Neural mechanisms of pelvic organ crosssensitization (2007). Neuroscience, Review). We use neuroanatomical, immunohistochemical,
electrophysiological and neuropharmacological methods to characterize the role of sensory
neural pathways in cross-sensitization between pelvic organs and chronic pelvic pain. This work
is supported by the NIH/NIDDK R01 grant DK077699.
Project 2. Role of hypoxia-inducible factors in the development of bladder dysfunction in
pediatric bladder outlet obstruction
Partial bladder outlet obstruction (PBOO) is a devastating clinical problem that causes
voiding dysfunction resulting in renal impairment, urinary tract infections, and urinary
incontinence. Obstruction can occur as a result of various anatomical and functional
abnormalities, and in pediatric patients it is usually associated with posterior urethral valves
(PUV) in boys. Despite advanced medical and surgical interventions, PUV remains a clinical
challenge; at least a third of PUV patients will progress to the end stage renal disease. PBOO
causes back pressure on the bladder which can initially undergo compensatory enlargement by
increasing bladder wall thickness with detrusor smooth muscle hypertrophy and/or hyperplasia
leading to alterations in bladder compliance. Chronic and excessive distension or overstimulated neuromuscular activity causes high pressure and strain in the bladder wall, leading to
ischemia and hypoxia. Eventually, contractile performance is lost and the bladder enters a
decompensated stage due to fibrosis and tissue denervation. Accumulating evidence suggests
that PBOO-induced pathogenesis is partly attributable to hypoxia in the obstructed bladders,
likely through the activity of Hypoxia-inducible factors (HIFs). We currently test the hypothesis
that pharmacological blockade of HIF pathways could reduce detrusor dysfunction following
PBOO.
Project 3. Mechanisms of mechanotransduction in the human detrusor
Mechanosensitivity of the detrusor is defined as the ability of smooth muscle cells to
generate mechanical activity independent of external stimuli. Activation of mechanosensitive
receptors on smooth muscle cells is the first step in initiating mechanotransduction in the
bladder wall with subsequent transmission of the signasl to sensory neurons and, further, to the
central nervous system. Pathological changes in bladder mechanotransduction lead to the
development of detrusor overactivity (DO) which is a co-symptom of several dysfunctions of the
lower urinary tract including overactive bladder, obstructed bladder, diabetic overactivity, urinary
incontinence, and bladder pain syndrome. This project is focused on the mechanisms of
impaired mechanosensation and mechanotransductionwhich may underlie detrusor overactivity
due to alterations in mechanotransduction between bladder smooth muscle cells and intrinsic
nerve fibers in the bladder wall. The study is supported by the NIH/NIDDK grant R01 DK
095817.
Project 4. Neurogenic bladder dysfunction in neurological disorders
Neurogenic bladder dysfunction often develops in patients with neurological disorders
such as multiple sclerosis, Parkinson`s disease, Alzheimer`s disease, etc. Bladder symptoms
present in 32–97% of patients with neurological disorders. They include urinary urgency, urinary
incontinence, nocturia, urinary hesitancy, overflow incontinence, a sensation of incomplete
emptying, frank urinary retention and a weak urinary stream. It is thought that neurogenic
bladder dysfunction develops due to lesions in the brain and/or spinal cord, or from the oss of
axons in the pathways that control bladder function. In approximately 5–10% of patients,
bladder symptoms are present at the onset of multiple sclerosis when there may be few lesions
identified in the spinal cord and/or brain. In patients with established MS, bladder symptoms are
prevalent and often associated with symptoms of bowel and sexual dysfunction. This research
is supported by P20 grant from the NIDDK (DK097819) as Colorado Center on Interdisciplinary
Research in Benign Urology (IR-BU, PI- Anna Malykhina).