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Receptors for neurotransmitters in Auerbach's plexus of Hirschsprung's disease ; A comparison with animal models

先天性巨结肠症奥尔巴赫丛中的神经递质受体；

基本信息

批准号：
09671237
负责人：
KANEMATSU Takashi
金额：
$ 1.22万
依托单位：
NAGASAKI UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

We examined the changes in receptors of neurotransmitters such as endothelin (EL) and substance P in the intestinal wall related to the dysfunction of large-intestinal motility in Hirselisprung disease and its animal model of congenital aganglionosis (AR) rat, the rat with a mutant endothelin ET_B receptor. We used our newly-developed method for analyzing the receptor dynamics ; the quantitative receptor-imaging system with three experimental techniques, 1) in vitro radioligand-binding technique for functional sites of receptors, 2) quantilative radioimnunohistochernical technique for sites of receptor proteins maturation, and 3) in situ hybridization technique for production sites of receptors with 35S-cRNA probes. We found the existence of ET_B receptors in the main principal cell (cholinergic neuronal cell body) in Auerbach's plexus, and small enteroglia in the colon of patients and AR rats. With the use of our methods, we confirmed the finding that ^1^2^5IRL162O, a selective radioligand for the ET_B receptor, merely bound to the section of colon with Aucrbach's plexus isolated from a patient with Hirschsprung's disease. In this case of patient, we failed to detect a compensatory increase of substance P receptor, using our method. Interestingly, in another patient with Hirschsprung's disease no abnormal binding of ^1^2^5I-1RL1620 was observed, however, a very lower amount of the expression of substance P receptor in Anerbach's plexus. Thus, we confirmed the pathopliysiological significance of the ETB receptor in the onset of Hirschsprung disease, and the possible another gene-defect in this disease. A factor regulating substance P receptor function may shed some light on the discovery of the heterogeneity of Hirschsprung's disease.

本研究观察了先天性巨结肠症（Hirselisprung disease，HD）及其动物模型先天性无神经节细胞症（congenital aganglionosis，AR）大鼠肠壁内皮素（endothelin，EL）和P B受体的变化。我们采用我们新开发的受体动力学分析方法：定量受体成像系统结合三种实验技术，1）体外放射配基结合技术用于受体功能位点，2）定量放射免疫组织化学技术用于受体蛋白成熟位点，3）原位杂交技术用于35 S-cRNA探针受体产生位点。结果表明，在奥尔巴赫氏神经丛的主要主细胞（胆碱能神经元胞体）和患者及AR大鼠结肠的小胶质细胞中均存在ET_B受体。用我们的方法，我们证实了ET_B受体的选择性放射性配体^1^2^5 IRL 162 O仅与从先天性巨结肠病人分离的带有Aucrbach氏丛的结肠切片结合。在这种情况下的病人，我们未能检测到的物质P受体的代偿性增加，使用我们的方法。有趣的是，在另一名先天性巨结肠患者中，没有观察到^1^2^5I-1 RL 1620的异常结合，然而，在Anerbach氏神经丛中，P物质受体的表达量非常低。因此，我们证实了ETB受体在先天性巨结肠发病中的病理生理学意义，并可能是先天性巨结肠的另一个基因缺陷。一种调节P物质受体功能的因子可能有助于揭示先天性巨结肠的异质性。