Physiological roles and gene expressions of CCK receptors in the regulation of bile-pancreatic secretion and gastric functions

CCK受体在调节胆胰分泌和胃功能中的生理作用和基因表达

• 批准号: 12470131
• 负责人: MIYASAKA Kyoko
• 金额: $ 8.64万
• 依托单位: Tokyo Metropolitan Institute of Gerontology
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470131/
• 关键词: CCK; CCK receptor; CCK-Areceptor; CCK-B receptor; gene; gallstone; pancreas; gene expression; 遺伝子解析; 遺伝子発現; 胆嚢; コレシストキニンA受容体; 分子機構; 膵臓; 消化器機能

The pancreatic size in adult OLETF rats was significantly lower than that in adult LETO rats ; however, there were no differences between CCK-A receptor(-/-) mice and wild-type mice. This finding indicates that the CCK-A receptor is more important for pancreatic natural growth in rats than it is in mice. Pancreatic bicarbonate secretion was produced by the administration of secretin in rats, whereas secretin failed to increase bicarbonate secretion in mice, and CCK increased bicarbonate secretion via CCK-A receptor in mice. Oral administration of trypsin inhibitor increased pancreatic size in rats within 5 days, whereas 14 days were required in mice. Lack of CCK-BR enhanced gastric emptying of a liquid load.Recently, we identified two sequence changes, a G to T change in nucleotide -128, and an A to G change in nucleotide -81, in the promoter region of the CCK-A receptor gene. The frequency of each polymorphism was more than 1%, and the homozygote (T/T, G/G) is associated with a signif … More icantly higher percent body fat and higher levels of serum insulin and leptin than are the other genotypes. Therefore, the CCK-A receptor polymorphism in the promoter region is considered to be one of single nucleotide polymorphisms (SNPs) related to weight control difficulties in obese subjects, and also to other factors such as lifestyle as well as eating habits. Recently, we found that this CCK-A receptor promoter polymorphism was corresponded to the disease process in chronic pancreatitis and gallstone patients. Using a luciferase reporter assay, we investigated whether or not the polymorphic promoter sequence in the CCK-A receptor gene affected CCK- receptor promoter activity. We found that the major polymorphic construct, pGL-315/+112 (GA), as well as the other two constructs, showed almost the same activity in transient transfection experiments. The polymorphic -128 G is also in the CpG dinucleotide sequence. If an effect of methylation, as shown in the case of rat CCK-A receptor expression, is also found in the case of human CCK-A receptor expression, this polymorphism may be revealed to have some effect on the transcription of this gene. In a recent study, we demonstrated that reduced methylation in the promoter region was related to the substantial expression of the CCK-AR gene. Less

成年OLETF大鼠的胰腺大小明显小于成年LETO大鼠；然而，CCK-A受体(-/-)小鼠和野生型小鼠之间没有差异。这一发现表明，CCK-A 受体对于大鼠胰腺的自然生长比小鼠更重要。通过给大鼠施用促胰液素来产生胰腺碳酸氢盐分泌，而促胰液素不能增加小鼠中碳酸氢盐的分泌，而CCK通过CCK-A受体增加小鼠中碳酸氢盐的分泌。口服胰蛋白酶抑制剂可在 5 天内增加大鼠的胰腺大小，而小鼠则需要 14 天。缺乏CCK-BR会增强液体负荷的胃排空。最近，我们在CCK-A受体基因的启动子区域中发现了两个序列变化，即核苷酸-128中的G至T变化和核苷酸-81中的A至G变化。每个多态性的频率超过 1%，并且与其他基因型相比，纯合子（T/T、G/G）与显着更高的体脂百分比以及更高水平的血清胰岛素和瘦素相关。因此，启动子区的CCK-A受体多态性被认为是与肥胖受试者体重控制困难以及其他因素如生活方式和饮食习惯相关的单核苷酸多态性(SNP)之一。最近，我们发现这种CCK-A受体启动子多态性与慢性胰腺炎和胆结石患者的疾病过程相对应。使用荧光素酶报告基因测定，我们研究了CCK-A受体基因中的多态性启动子序列是否影响CCK-受体启动子活性。我们发现主要的多态性构建体pGL-315/+112 (GA)以及其他两种构建体在瞬时转染实验中表现出几乎相同的活性。多态性-128 G 也在CpG 二核苷酸序列中。如果在人CCK-A受体表达的情况下也发现了甲基化的影响，如在大鼠CCK-A受体表达的情况下所示，则可以揭示该多态性对该基因的转录具有一些影响。在最近的一项研究中，我们证明启动子区域甲基化的减少与CCK-AR基因的大量表达有关。较少的

项目成果

Suzuki S, Kanai S, Miyasaka K: "Regulation of pancreatic secretion by vagal nerve during short-term duct occlusion in conscious rats"Pancreas. 20. 94-101 (2000)

Suzuki S、Kanai S、Miyasaka K：“意识大鼠短期导管闭塞期间迷走神经对胰腺分泌的调节”胰腺。

Ohta M, Miyasaka K, et al.: "Mechanism of delayed gastric emptying in naturally occurring CCK-A receptor gene knockout (OLETF) rats"Jpn J Physiol. 50. 443-448 (2000)

Ohta M、Miyasaka K 等：“自然发生的 CCK-A 受体基因敲除 (OLETF) 大鼠胃排空延迟的机制”Jpn J Physiol。

Suzuki S, Miyasaka K: "Induction of acute pancreatitis by cerulein in human IL-6 gene transgenic mice"Pancreas. 21. 86-92 (2000)

Suzuki S、Miyasaka K：“人 IL-6 基因转基因小鼠中雨蛙素诱导急性胰腺炎”胰腺。

Kawanami T, Miyasaka K: "Oral administration of a synthetic trypsin inhibitor increases pancreatic duct function in CCK-A receptor-deficient rats"Pancreas. 20. 394-400 (2000)

Kawanami T、Miyasaka K：“口服合成胰蛋白酶抑制剂可增强 CCK-A 受体缺陷大鼠的胰管功能”胰腺。

Miyasaka K: "Inhibitory effect of somatostatin on CCK release is independent of luminal LCRF content in conscious rats"Pancreas. 23. 414-420 (2001)

Miyasaka K：“生长抑素对 CCK 释放的抑制作用与清醒大鼠胰腺中的管腔 LCRF 含量无关。”