Lower urinary tract (LUT) dysfunction is the most common cause of end-stage renal disease in children. Although several genetic pathways controlling LUT structure have been identified, the genetic pathways controlling the coordinated contraction of LUT musculature, a process essential for moving wastes out of the body, remain poorly understood. This is due, in large part, to the absence of techniques to assess LUT motility in real time in intact tissues such as the ureter, bladder and urethra. We have developed a novel ureter explant system and video microscopic and optical mapping protocols to analyze ureteral smooth muscle contractile and excitation patterns and discovered that the initiation of electrical activity driving coordinated, proximal to distal contraction is dependent on pacemaker cells that express hyperpolization activated cation channels. This Resource Center will apply our state-of-the-art functional imaging techniques to existing mouse mutants exhibiting LUT dysfunction to determine if aberrant smooth muscle function plays a causative, pathological role. Results of these studies will provide much needed model systems to identify the molecular mechanisms underlying coordinated LUT motility and ultimately yield novel drug therapies to treat inborn or acquired defects in this process.
This Resource Development Center for Functional Imaging of urinary tract smooth muscle integrates the expertise of murine geneticists, urologists and systems physiologists under a common infrastructure dedicated to the study of lower urinary tract dysfunction, a leading cause of renal damage in humans. The center will facilitate the use of real time imaging techniques for the functional analyses of mutant mouse lines with complex urologic defects and provide much needed model systems to test drugs that can alleviate urinary tract motility defects in humans.
|Herzlinger, Doris; Hurtado, Romulo (2014) Patterning the renal vascular bed. Semin Cell Dev Biol 36:50-6|
|Hurtado, Romulo; Bub, Gil; Herzlinger, Doris (2014) A molecular signature of tissues with pacemaker activity in the heart and upper urinary tract involves coexpressed hyperpolarization-activated cation and T-type Ca2+ channels. FASEB J 28:730-9|
|Herzlinger, Doris (2011) Upper urinary tract pacemaker cells join the GLI club. J Clin Invest 121:836-8|
|Hurtado, Romulo; Bub, Gil; Herzlinger, Doris (2010) The pelvis-kidney junction contains HCN3, a hyperpolarization-activated cation channel that triggers ureter peristalsis. Kidney Int 77:500-8|