CONTROL OF RECTOANAL MOTILITY

胃肠道的直肠肛门区控制着胃肠道内容物的最终储存、运输和排出。这些功能要求该区域逐渐更远端的节段的收缩行为有实质性的差异。本研究探讨了犬和小鼠胃肠道自发性运动模式的机制和直肠肛门环肌兴奋性神经的作用。这些研究的总体假设是，起搏器活动的性质、神经元的神经支配以及去甲肾上腺素(NE)和乙酰胆碱(ACh)的作用发生了根本性的变化，这使得直肠肛门区的相邻部分可以执行互补但不同的功能。将使用放射性配基结合技术测量膜电位和收缩活性以及受体密度。这些数据将与免疫组织化学和免疫细胞化学测量相比较，以确定可能的起搏细胞(即Cajal或ICC的间质细胞)及其与内源性和外源性神经的关系。将使用犬模型的8厘米区域和小鼠模型的1厘米区域，包括直肠和肛门内括约肌(IAS)。本建议的具体目的是：1)比较起搏电位与ICC的空间分布；2)表征直肠肛门区功能性运动神经支配随距离的变化；3)确定神经的解剖分布及其与ICC分布的关系；4)利用功能测量和放射配基结合技术评估直肠肛门区的肾上腺素能和毒鼠碱反应；5)利用基因敲除小鼠和器官培养技术评估起搏。数以百万计的美国人患有直肠肛门区疾病，这些疾病会导致便秘或大便失禁。这项建议中概述的实验将提供有关直肠肛门运动及其神经控制的解剖和生理特征的重要新信息。通过这样做，我们可能会帮助未来的研究，以了解这些功能是如何在疾病状态下改变的。

The rectoanal region of the GI tract regulates the final storage, transport and evacuation of the GI contents. These functions require substantial differences in the contractile behavior of progressively more distal segments of this region. This study investigates the mechanisms underlying spontaneous motility patterns and the actions of excitatory nerves in rectoanal circular muscle of the dog and mouse gastrointestinal tract. The overall hypothesis for these studies is that fundamental changes occur in the nature of pacemaker activity, neuronal innervation and the actions of norepinephrine (NE) and acetylcholine (ACh) which permit adjacent portions of the rectoanal region to perform complimentary but distinct functions. Membrane potential and contractile activity will be measured as well as receptor density using radioligand binding techniques. These data will be compared to immunohistochemical and immunocytochemical measurements to identify putative pacemaker cells (i.e., interstitial cells of Cajal or ICC) and their relationship to intrinsic and extrinsic nerves. An 8 cm region of the canine model and a 1 cm region of the mouse model encompassing both the rectum and internal anal sphincter (IAS) will be used. The specific aims of this proposal are: 1) To compare the spatial distribution of pacemaker potentials to ICC, 2) To characterize the changes which occur in functional motor innervation with distance in the rectoanal region, 3) To determine the anatomical distribution of nerves and their relationship to the distribution of ICC, 4) To evaluate postjunctional adrenergic and muscarinic responses in the rectoanal region using functional measurements and radioligand binding techniques, 5) To evaluate pacemaking using knockout mice and organ culture techniques. Millions of Americans suffer from diseases of the rectoanal region which lead to either constipation or fecal incontinence. The experiments outlined in this proposal will provide important new information regarding the anatomical and physiological characteristics which underlie rectoanal motility and its nervous control. In so doing we may aid future studies directed toward understanding how these functions become altered in disease states.