Elucidation fo molecular mechanism of pancreatic befa ceel differentiation using fissue-specific koock-out mice for the regeneration of beta ceas

使用组织特异性敲除小鼠再生β-ceas来阐明胰腺befa细胞分化的分子机制

• 批准号: 18591021
• 负责人: HOSODA Kiminori
• 金额: $ 2.48万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591021/
• 关键词: βcell; Notch; Rbp-i; development; 糖尿病; インスリン; 膵臓; 再生

We inactivated Rbp-j by crossing Rbp-j floxed mice with Pdx. cre or Rip.cre transgenic mice. The loss of Rbp-j at the initial stage of pancreatic development induced accelerated alpha and PP cell differentiation and a concomitant decrease in the number of Neurogenin3 (Ngn3)-positive cells at E11.5. Then at E15, elongated tubular structures expressing ductal cell markers were evident; however, differentiation of acinar and all types of endocrine cells were reduced During later embryonic stages, compensatory acinar cell dfferentiation was observed The resultant mice exhibited insulin-deficient diabetes with both endocrine and exocrine pancreatic hypoplasia In contrast, the loss of Rbp-j specifically in beta cells did not affect bete cell number and function.We also generated mice in which the Rbp-j gene was inactivated in Ptfla-expressing cells using Ptfla.cre mice. The timing of the Cre-mediated deletion in Rbp-j(f/f) Ptfla.cre mice is 1 day later than that in Rbp-j(f/f) Pdx.cre mice. In Rbp-j(f/f) Ptfla.cre mouse pancreases, at E13.5, the reduced Hesl expression was accompanied by reduced epithelial growth, but premature endocrine cell differentiation was minimal. At E15.5, Pdxl expression was repressed and acinar cell differentiation was reduced, but an increase in acinar cell proliferation was observed during the per natal period. Thus, our analyses indicate that Notch/Rbp-j signaling prevents premature differentiation of pancreatic progenitor cells into endocrine and ductal cells during early development of the pancreas.Our study indicates that in addition to its role in preventing premature differentiation of early endocrine cells, Rbp-j regulates epithelial growth, Pdxl expression, and acinar cell differentiation during mid-pancreatic development.

我们将Rbp-j与Pdx杂交，使Rbp-j失活。或者Rip。转基因小鼠。在胰腺发育初期，Rbp-j的缺失导致α和PP细胞的加速分化，同时在E11.5时，Ngn3阳性细胞的数量减少。E15时可见表达导管细胞标记物的细长管状结构；然而，腺泡细胞和所有类型的内分泌细胞的分化都减少了。在胚胎后期，观察到代偿性腺泡细胞分化。由此产生的小鼠表现为胰岛素缺乏型糖尿病，同时伴有内分泌和外分泌胰腺发育不全。相反，β细胞中特异性Rbp-j的缺失并不影响β细胞的数量和功能。我们还使用Ptfla在表达Ptfla的细胞中产生了Rbp-j基因失活的小鼠。cre老鼠。cre介导的Rbp-j(f/f) Ptfla缺失的时间。cre小鼠比Rbp-j(f/f) Pdx晚1 d。cre老鼠。在Rbp-j(f/f) Ptfla中。cre小鼠胰腺，在E13.5时，Hesl表达降低伴随着上皮生长减少，但早期内分泌细胞分化最小。在E15.5时，Pdxl表达被抑制，腺泡细胞分化减少，但在出生期间观察到腺泡细胞增殖增加。因此，我们的分析表明，Notch/Rbp-j信号通路在胰腺早期发育过程中阻止胰腺祖细胞过早分化为内分泌细胞和导管细胞。我们的研究表明，Rbp-j除了在预防早期内分泌细胞过早分化中发挥作用外，还在胰腺中期发育过程中调节上皮生长、Pdxl表达和腺泡细胞分化。

项目成果

Images in cardiovascular medicine. Mitochondrial cardiomyopathy evaluated with cardiac magnetic resonance.

心血管医学中的图像。

• 发表时间: 2007
• 期刊: Circulation 116
• 作者: Itoh H;Yamamoto T;Sugihara H;Saotome T;Eguchi Y;Asai T;Horie M.;Nakanishi Michio
• 通讯作者: Nakanishi Michio

A case of secretin-responsive insulinoma with low serum C-peptide levels.

血清 C 肽水平低的促胰液素反应性胰岛素瘤一例。

• 发表时间: 2007
• 期刊: Endocr J. Feb;54(1)
• 作者: Fujikura J;Hosoda K;Noguchi M;Ebihara K;Masuzaki H;Hirata M;Fujimoto K;Doi R;Iwanishi M;Nakao K.
• 通讯作者: Nakao K.

膵特異的Rbp-jノックアウトマウスの検討

胰腺特异性 Rbp-j 敲除小鼠的检查

• 发表时间: 2008
• 作者: 藤倉純二;細田公則;川口義弥;野口倫生;岩倉浩;冨田努;小鳥真司;森栄作;泰江慎太郎;石井崇子;岡田定規;目下部徹;平田雅一;海老原健;益崎裕章;谷垣健二;矢部大介;中尾一和
• 通讯作者: 中尾一和

Notch/Rbp-j signaling prevents premature endocrine and ductal cell differentiation in the pancreas

• DOI: 10.1016/j.cmet.2005.12.005
• 发表时间: 2006-01-01
• 期刊: CELL METABOLISM
• 影响因子: 29
• 作者: Fujikura, J;Hosoda, K;Nakao, K
• 通讯作者: Nakao, K

メタボリックシンドロームと脂肪毒性

代谢综合征和脂毒性

• 发表时间: 2007
• 作者: 細田 公則;海老原 健;中尾 一和
• 通讯作者: 中尾 一和