Real Time Imaging of Urinary Tract Smooth Muscle Function

描述(申请人提供)：下尿路(LUT)功能障碍是儿童终末期肾脏疾病最常见的原因。尽管已经确定了几条控制LUT结构的遗传路径，但控制LUT肌肉系统协调收缩的遗传路径仍然知之甚少。LUT肌肉系统是将废物移出体外所必需的过程。这在很大程度上是由于缺乏实时评估输尿管、膀胱和尿路等完整组织中LUT运动的技术。我们开发了一种新的输尿管移植系统以及视频显微镜和光学标测方法来分析输尿管平滑肌的收缩和兴奋模式，发现电活动的启动驱动协调的近端到远端的收缩依赖于表达超极化激活的阳离子通道的起搏细胞。该资源中心将把我们最先进的功能成像技术应用于表现出LUT功能障碍的现有小鼠突变，以确定异常的平滑肌功能是否起到致病和病理作用。这些研究的结果将提供急需的模型系统，以确定协调LUT运动的分子机制，并最终产生治疗这一过程中先天或后天缺陷的新药物疗法。

DESCRIPTION (provided by applicant): 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.