| Project/Area Number |
12670475
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Nagoya University |
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Principal Investigator |
NARUSE Satoru Nagoya University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (50180550)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIGURO Hiroshi Nagoya University, Research Center Health, Physical Fitness, and Sports, Research Associate, 総合保健体育科学センター, 助手 (90303651)
KITAGAWA Motoji Nagoya University, University Hospital, Research Associate, 医学部附属病院, 助手 (80262898)
FURUYA Sonoko Nagoya University, National Institute for Physiological Sciences, Research Associate, 生理学研究所, 助手 (20096952)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2002: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2001: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2000: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | chronic pancreatitis / CFTR / sweat chloride concentration / poly T / TG repeat / pancreatic duct cell / HCO_3^- secretion / SLC26 transporter / 膵HCO_3^-輸送 / 細胞内電位 / Cl^--HCO_3^-交換 / 単離小葉間膵管 / 細胞内Cl^-濃度 / 5-hydroxytriptamine / Na^+-HCO_3^-cotransport / 水チャネル / 嚢胞線維症 / CFTRクロライドチャンネル / CFTR遺伝子異常 / ポリT多型 / トランスジュニックマウス / 単離導管細胞 / 水分泌測定 |
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| Research Abstract |
1. We have investigated whether mutations of the CFTR (cystic fibrosis transmembrane conductance regulator) gene are related to chronic pancreatitis in Japanese.
2. To estimate the function of CFTR, we established a simple and non-invasive method to measure Cl^- concentrations in the sweat. Of 25 patients with chronic pancreatitis, 56% had sweat Cl^- levels over 60 mmol/L, a level consistent with the diagnosis of cystic fibrosis. This suggests that the impaired CFTR function underlies about a half of chronic pancreatitis in Japanese.
3. None of 20 major mutations in Caucasians were found in healthy subjects and patients with chronic pancreatitis. Polymorphisms at the junction of intron8 and exon9 (TG) repeats were unique to Japanese, which may explain CFTR dysfunction in patients with chronic pancreatitis.
4. To investigate the secretory mechanism of HCO_3^- from pancreatic duct cells, we have measured intracellular concentrations of HCO_3^- and Cl^- and membrane potential in interlobular ducts isolated from guinea-pig pancreas. We proposed a new model ; (a) when the luminal HCO_3^- concentration is below-70 mM, HCO_3^- secretion is supported by Cl^--HCO_3^- exchange and (b) when the luminal HCO_3^- concentration is higher than 70 mM, it is mediated by a HCO_3^- conductance, most likely CFTR.
5. CFTR and SLC26 family of transporters were co-expressed in Xenopus oocytes or HEK (Human Embryonic Kidney) 293 cells. We found that the SLC26 transporters work as electrogenic Cl^-HCO_3^- exchangers and are regulated by CFTR.
6. RT-PCR analysis of isolated ducts from rat pancreas revealed the expression of AQP1 in pancreatic duct cells. The osmotic water permeability of the ductal epithelium was reduced by either basolateral or luminal. application of HgCl_2. AQP1 of the known water channels appears to be the main water pathway in pancreatic ductal epithelium. Immunohistochemistry revealed heterogeneous expression of AQP1 in rat duct cells.
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