FUNCTIONAL ADAPTATIONS OF INTESTINAL SMOOTH MUSCLE

这项研究的总体目标是了解 发生在收缩中的适应的细胞基础 平滑肌对功能变化的反应过程 需求。我们将从分析一个有趣的先天 先天性巨结肠症--肠平滑肌紊乱 发生了哪两种截然不同的适应性变化。这个 直肠神经节细胞减少，特别是缺乏非肾上腺素能， 非胆碱能抑制性肠神经。结果，直肠 音调收缩，导致明显的胀大和 近端结肠肌肉肥大，或“巨结肠”。 因此，这两个区域的平滑肌肉都经历了功能变化： 直肠呈现紧张性收缩状态，而结肠 经历肥大。一种定义明确的小鼠模型 先天性巨结肠症和巨结肠在 用正常小鼠进行实验性狭窄实验，以期 解决问题：在多大程度上适应新的 通过结构改造表达的功能需求，以 机械力化学转导过程的改进或 它的规定是什么？我们将学习基本的机械、化学和 发生在平滑肌中的超微结构变化， 确定(1)机械性能，例如 产生力量，缩短和做机械功，通过 长度-张力和力-速度特性；(2) 高能磷酸盐使用之间的基本关系 和机械产量，以确定经济 劳动生产率和劳动产出效率。 高能磷酸盐的时间分辨直接测量 与平稳状态下的各种机械状态相关的用法 肌肉，以及测量稳定性的标准方法- 将使用国家氧气消耗和乳酸生产；(3) 钙调节收缩的机制，通过 肌球蛋白20,000道尔顿轻链的磷酸化 其他钙依赖的过程；(4)超微结构研究将 使我们能够确定作用力/细胞，细胞尺寸 对于肥大和/或增生的定义，以及 可收缩的细丝和细胞骨架元素 力量传递。在所有这些研究中，比较将是 由动物的肌肉片段制成，实验上- 诱发性和先天性巨结肠，先天性狭窄 直肠和其正常的相应节段 一窝产仔。

The overall objective of this research is to gain an understanding of the cellular basis of adaptations that occur in the contractile process of smooth muscle in response to changes in functional demand. We will begin by analyzing an interesting congenital disorder of intestinal smooth muscle, Hirschsprung's disease, in which two very different adaptive changes have occurred. The rectum is hypoganglionic, and specifically lacks non-adrenergic, non-cholinergic inhibitory enteric nerves. As a result, the rectum is tonically constricted which leads to marked distension and muscular hypertrophy of the proximal colon, or "megacolon". Thus, smooth muscles of both regions undergo functional change: the rectum assumes a state of tonic contraction and the colon undergoes hypertrophy. A well-defined murine model of Hirschsprung's disease and one in which megacolon is induced in normal mice by experimental stenosis will be used in order to address the question: to what extent are adaptations to new functional demands expressed through structural remodelling, to modification of the mechanochemical transduction process or to its regulation? We will study the basic mechanical, chemical and ultrastructural changes that occur in the smooth muscle, determining the (1) mechanical properties, such as the ability to generate force and shorten and do mechanical work, through the length-tension and force-velocity characteristics, respectively; (2) fundamental relationships between high-energy phosphate usage and mechanical output, in order to determine the economy of force production and efficiency of work output. Time-resolved, direct measurements of high-energy phosphate usage associated with various mechanical states in smooth muscle, and standard methods for the measurement of steady- state oxygen consumption and lactate production will be used; (3) mechanisms whereby contraction is regulated by calcium, through phosphorylation of the 20,000-dalton light chains of myosin and other calcium-dependent processes; (4) ultrastructural studies will allow us to determine force production/cell, cellular dimensions for a definition of hypertrophy and/or hyperplasia, and changes in contractile filament and cytoskeletal elements which bear on force transmission. In all of these studies, comparisons will be made among muscle segments from animals with experimentally- induced and congenital megacolon, the congenitally constricted rectum and the corresponding segments from their normal littermates.