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Welcome to the Malykhina Lab
Anna Malykhina, PhD
Research Interests
Research in the Malykhina lab studies physiology and pathophysiology of lower urinary tract with particular emphasis on the neural mechanisms of urological chronic pelvic pain syndrome (UCPPS), pelvic organ cross-sensitization, neurogenic voiding dysfunction in neurodegenerative disorders (multiple sclerosis), and mechanosensitivity/mechanotransduction in animal and human urinary bladder.
Active Research Projects
Neurogenic Bladder Dysfunction in Neurodegenerative Disorders
Patients with neurological disorders such as multiple sclerosis (MS), Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis develop a wide range of lower urinary tract symptoms, including urinary urgency, urinary incontinence, nocturia, a sensation of incomplete emptying, and a weak urinary stream. We established a new mouse model of neurogenic bladder dysfunction induced by coronavirus as a model of multiple sclerosis (CIE model), and evaluated the mechanisms of voiding dysfunction in both animal studies and patients with MS experiencing LUTS. Our studies provided evidence that differential neurodegenerative phenotypes triggered by a coronaviral infection caused distinct types of voiding dysfunction. The behavioral and functional changes in CIE mice included demyelination in the spinal centers controlling micturition, changes in the expression of inflammatory mediators, altered purinergic responses of bladder contractions, and distinct neuroinflammatory transcriptomic profiles of macrophages and cytotoxic cells in the CNS and urinary bladder (UB). We currently work on a characterization of spatial proteomic immune cell profiles in the CNS and urinary bladder to localize key cellular targets in the bladder wall contributing to altered voiding function.
The Role of Mechanosensitive Ion Channels in Detrusor Overactivity
Bladder stretch during filling triggers mechanosensory signaling from bladder myocytes to the afferent nerve fibers, the process known as “myocyte-afferent crosstalk”. Pathophysiological changes in myocyte-afferent mechanotransduction may lead to the development of overactive lower urinary tract symptoms (LUTS) which are part of several disorders including overactive bladder (OAB), neurogenic or obstructed bladder, diabetic overactivity, and bladder pain syndrome. Our previous work provided evidence that one of the molecular determinants of myocyte-afferent mechanosensation in the human detrusor is TREK-1 channel, a member of mechanogated two-pore domain potassium (K2P, KCNK) channels. We confirmed that TREK-1 expression and function were diminished in patients with overactive LUTS. In vitro contractility studies from TREK-1 KO mice revealed an elevated basal muscle tone, enhanced spontaneous activity and increased contractile responses in the detrusor. We use human bladder specimens from patients with overactive LUTS, human DRG, TREK-1 KO animals, two animal models of overactive LUTS, as well as newly created in our laboratory genetically modified mice for these studies.
Mechanisms of Pelvic-Organ Cross-Sensitization and Chronic Pelvic Pain
Chronic pelvic pain (CPP) is a common symptom of many urologic and gastrointestinal disorders including interstitial cystitis/bladder pain syndrome (IC/BPS) and irritable bowel syndrome (IBS). Our group was at the forefront of the research efforts aimed at understanding the mechanisms underlying co-morbid CPP disorders and provided initial evidence that cross-sensitization via neural pathways triggers the development of neurogenic inflammation in the pelvis and chronic pelvic pain of unknown etiology. We determined that transient colonic inflammation causes neurogenic bladder dysfunction evaluated by cystometry, triggers hyperexcitability of bladder sensory and spinal neurons, increases pro-inflammatory neuropeptides in the bladder, and alters detrusor contractility. We currently test the hypothesis that neurogenic bladder dysfunction develops due to aberrant signal transduction in sensory neurons (peripheral cross-sensitization), interference of pain pathways with the micturition reflex in the brainstem (central cross-sensitization), and neuronal epigenetic changes underlying the transition from acute to chronic pelvic pain.