Genomic analysis of the causative gene for the aganglionosis rat and application of this rat to the pharmacological analysis

内皮素B型受体（Ednrb）基因在神经节病大鼠肺组织中的表达明显低于对照组。此外，与对照组相比，神经节病大鼠的Ednrb cDNA PCR产物的大小更短。通过测定神经节病大鼠Ednrb cDNA的编码序列，并与对照大鼠比较，发现存在两种缺失的cDNA；一个在第20到483个核苷酸之间被删除，另一个在第213到483个核苷酸之间被删除。从这些结果可以看出，神经节病的原因是Ednrb基因表达的显著减少和微弱表达的残余Ednrb mRNA的缺失。我们试图研究内皮素在神经节病大鼠骨髓中调节IL-6产生的作用。然而，内皮素不能增加骨髓来源的基质细胞产生IL-6，即使是正常的对照幼崽。因此，不可能检测内皮素在该突变大鼠骨髓中的作用。然而，我们可以阐明其他血压调节激素，血管活性肠肽（VIP）和垂体腺苷酸环化酶激活多肽（PACAP）调节骨髓中IL-6的产生。

Expression of endothelin type B receptor (Ednrb) gene in the lung was extremely lower in aganglionosis rats compared to control rats. Further, the size of PCR products of the Ednrb cDNA were shorter in aganglionosis rats compared to that of control rats. By determining the coding sequence of the Ednrb cDNA in aganglionosis rats and comparing it with that of control rats, two kinds of deleted cDNAs were found to be present ; one is deleted between the 20th and 483rd nucleotide and another is deleted between the 213th and 483rd nucleotide. From these results, it is suggested that the cause of aganglionosis is due to a significant decrease in the Ednrb gene expression and deletion of the faintly expressed residual Ednrb mRNA.We tried to examine a role of endothelin in the regulation of IL-6 production in the bone marrow of aganglionosis rats. However, endothelin could not augment IL-6 production by bone marrow-derived stromal cells prepared even from control normal littermates. Thus, it was impossible to examine the effect of endothelin in the bone marrow of this mutant rat. However, we could elucidate that other blood pressure-regulating hormones, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) regulate IL-6 production in the bone marrow.