Development of novel therapeutics targeting the function of intestinal cells of Cajal in gastrointestinal motility disorder

开发针对胃肠动力障碍中 Cajal 肠细胞功能的新型疗法

基本信息

批准号：
11557042
负责人：
SHINOMURA Yasuhisa
金额：
$ 8.45万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Interstitial cells of Cajal (ICCs) are found as networks of cells associated with neuronal plexuses in gastrointestinal tract. Recent studies have provided evidence that ICCs function in the gut as pacemaker cells responsible for the generation of spontaneous electrical activity. We have shown the deficiency of ICCs and the decrease in the contractile activity of the intestine in spontaneous mutant rats with a small deletion at the tyrosine kinase domain of c-kit. We have also shown the deficiency of ICCs in patients with a myopathic form of chronic intestinal pseudo-obstruction. Most types of chronic intestinal pseudo-obstruction do not respond to conventional prokinetic drugs. Therefore, methods of novel therapeutics need to be developed by targeting the molecules associated with the regulation of proliferation, differentiation and function of ICCs. We are investigating the mechanism of the regulation of proliferation, differentiation and function of ICCs. We have established in vitro culture system for ICCs isolated from mouse intestine and intestinal stromal cell line. Stem cell factor (SCF), which is a ligand of c-kit, stimulated the proliferation of ICCs from day-8 postcoitus embryos. SCF did not stimulate the proliferation of ICCs from day-6 postpartum neonates but SCF was needed for their survival. We have developed stromal cell lines originating from the small intestine of the mouse. The stromal cells transfected with c-kit complementary DNA showed the tendency to differentiate to ICCs. We are going to identify the molecules that can be targeted to induce differentiation.

Cajal（ICC）的间质细胞被发现是胃肠道中与神经元丛有关的细胞网络。最近的研究提供了证据，表明ICC在肠道中起作用，是起搏器细胞，负责自发电活动的产生。我们已经显示了ICC的缺陷以及在自发性突变大鼠中肠的收缩活性的减少，在C-KIT的酪氨酸激酶结构域中具有小的缺失。我们还显示了ICC缺乏慢性肠道伪腹部肌病形式的患者。大多数类型的慢性肠道伪腹结构都不对常规的原始药物做出反应。因此，需要通过靶向与ICC的增殖，分化和功能相关的分子来开发新的治疗方法。我们正在研究ICC的增殖，分化和功能的调节机制。我们已经建立了从小鼠肠道和肠道基质细胞系中分离出的ICC的体外培养系统。干细胞因子（SCF）是C-KIT的配体，刺激了ICC从第8天的胚胎胚胎的增殖。 SCF并未刺激ICC从产后新生儿的增殖，但需要SCF才能生存。我们已经开发出源自小鼠小肠的基质细胞系。用C-KIT互补DNA转染的基质细胞显示出与ICC分化的趋势。我们将确定可以靶向诱导分化的分子。