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A Role of c-kit tyrosinekinase of physiological development of the gastrointestinal pacemaker activity

c-kit酪氨酸激酶对胃肠起搏器活性生理发育的作用

基本信息

批准号：
06454163
负责人：
NISHI Katsuhide
金额：
$ 4.54万
依托单位：
KUMAMOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

项目摘要

As to origin of electrical and mechanical rhythmicity in the gastrointestinal tract, a class of specialized cells, often referred to as interstitial cells (IC) have been suggested to serve as pacemaker cells However, the function of ICs has been difficult to investigate in intact muscles because of the structural complexities of GI muscle and the IC network. We took a different approach to explore function of the ICs in the intestine. Results are as follows, 1) A certain type of cells in smooth muscle layrs of developing gastrointestinal tract in the mouse expresses Kit-gene which is a proto-oncogene encoding a receptor tyrosine in PDGF/CSF-I receptor family and in vitro injection of a neutralizing antibody (ACK2) for the proto-oncogene product, Kit protein, during the first few days after birth reduced the number of the Kit-expressing cells, which was accompanied by impairment of development of normal rhythmic mechanical activity in the mouse intestine, 2) ACK2 specifically labels int … More erstitial cells (ICs) in the mouse GI tracts, and ACK2-treatment induces a loss of electrical slow wave activity and depolarization of the membranes of smooth muscle cells, 3) we have succeeded in isolating ICs in primary culture of the mice small intestine and recorded spontaneously active electrical currents from these primary cultured ICs, 4) Both of the voltage-sensitive Na^+ and Ca^<2+> currents were not observed clearly in the all c-kit ^+ cells tested, but the rhythmic fluctuation of membrane voltage was observed under the current-clamp condition, where only Cl^- permeates, 5) In the ileum of neonates on the day of birth (day 0 pp) which did not show any spontaneous contractile activity, ACh (>10^<-8>M) induced a dose-related sustained contraction, but the contractile responses to ACh declined in sensitivity each day after birth in the control mice, while ileum of ACK2-treated animals did not show a decrease in the sensitivity to ACh as well as prostaglandin E1 and F2a. These observations indicate that the kit--signaling pathway is important in the development of ICs as pacemaker cells in the intestinal tract. Impairment of development of the IC network would not only affect GI motility but also affect pharmacological characteristics of the ileac smooth muscle. Less

关于胃肠道电节律和机械节律性的起源，人们建议将一类特殊的细胞，通常称为间质细胞(IC)作为起搏细胞，但由于GI肌和IC网络的结构复杂性，在完整的肌肉中很难研究IC的功能。我们采取了一种不同的方法来探索肠道内ICs的功能。结果如下：1)小鼠发育中的胃肠道平滑肌层中的某类细胞表达原癌基因Kit-基因，Kit-基因是一种编码pdgf/csf-I受体家族受体酪氨酸的原癌基因，出生后头几天注射针对该原癌基因产物Kit蛋白的中和抗体(Ack2)会减少表达Kit的细胞的数量，并伴随着小鼠肠道正常节律性机械活动的发育障碍；2)ack2特异性标记…3)我们成功地分离了小鼠小肠原代培养的ICs，并记录到这些ICs的自发激活电流；4)电压敏感型Na~(++)和Ca~(2+)&gt；在所有受试的c-kit^+细胞中均未观察到明显的电流，但在电流钳条件下观察到膜电压的节律性波动。5)出生当天(第0天)，未显示任何自发收缩活动的新生儿回肠，ACh(&gt；10^&lt；-8&gt；M)引起剂量相关的持续性收缩，但对照组小鼠对ACh的收缩反应在出生后每天都有所下降，而ACK2处理的小鼠回肠对ACh的敏感性没有下降，也没有表现出前列腺素E_1和F2a的停滞。这些观察表明，KIT--信号通路在ICs作为肠道起搏细胞的发育过程中起着重要的作用。IC网络发育障碍不仅会影响胃肠动力，还会影响回肠平滑肌的药理特性。较少