KINETICS OF COLONIC SMOOTH MUSCLE RELAXATION

这份提案描述了一项旨在 让候选人成为一名独立的生物医学研究员。这个 候选人已经选择了非常适合作为导师的赞助商，并且 各自领域的专家。胡里奥·维加拉博士是钙控制方面的专家 机制和成像技术和小威廉·J·斯内普博士。是一种 是平滑肌生理学和病理生理学方面的专家。候选人 试图回答这个问题：cAMP通过 主要作用于细胞内钙离子或直接作用于肌动蛋白肌球蛋白。 桥牌队形？为了实现这一目标，需要两个阶段的研究和 提出了培训的建议。在第一阶段，候选人将进行正式的 细胞和肌肉生理学方面的课程工作以及参与 加州大学洛杉矶分校生理学系丰富的学术环境。 候选人将开发一个将钙和等长曲线联系起来的动力学模型。 兔结肠环状肌条中力的瞬变。在阶段中 第二，建议的动力学模型将被用于定量评估 CAMP在平滑肌收缩和松弛中的作用。具体的 实验目标是：1)测量细胞内钙和等长 同时应激，2)用两个钙验证该方法 灵敏染料(FLOO-3和INDO-1)，3)测定动力学参数 这些钙和力的瞬变，4)评估 光解释放的cAMP(笼养cAMP)对测定的动力学 关系，以及5)与cAMP介导的 肌球蛋白轻链激酶生物化学研究的收缩装置。 然而，更好地理解控制 平滑肌的收缩和松弛可能会导致重要的、新的 结肠运输和运动障碍患者的治疗 如特发性便秘和肠易激综合征。

This proposal describes a course of training and research designed to establish the candidate as an independent biomedical investigator. The candidate has chosen sponsors who are well suited as mentors and are experts in their field. Dr. Julio Vergara is an expert in calcium control mechanisms and imaging techniques and Dr. William J. Snape, Jr. is an expert in smooth muscle physiology and pathophysiology. The candidate seeks to answer the question: Does cAMP relax colonic smooth muscle through a primary effect on cytosolic calcium or directly on actin myosin cross- bridge formation? To accomplish this goal, two phases of research and training are proposed. During Phase I, the candidate will pursue formal course work in cell and muscle physiology as well as participating in the academically enriched environment of the UCLA Department of Physiology. The candidate will develop a kinetic model relating calcium and isometric force transients in rabbit colonic circular muscle strips. During Phase II, the proposed kinetic model will be used to quantitatively assess the role of cAMP on smooth muscle contraction and relaxation. The specific experimental aims are: 1) to measure intracellular calcium and isometric stress simultaneously, 2) to validate this method with two calcium sensitive dyes (fluo-3 and indo-1), 3) to measure the kinetic parameters of these calcium and force transients, 4) to assess the effect of photolytically released cAMP (caged cAMP) on the measured kinetic relationships, and 5) to correlate cAMP-mediated regulation of the contractile apparatus to biochemical studies of myosin light chain kinase. It is though that a better understanding of the mechanisms that control smooth muscle contraction and relaxation may lead to important, new treatments in patients with disorders of colonic transit and motility such as idiopathic constipation and the irritable bowel syndrome.