Identification of a novel therapeutic target that produces irreversible diabeticg lucotoxicky

鉴定产生不可逆糖尿病糖毒性的新治疗靶点

• 批准号: 18390100
• 负责人: KOJIMA Hideto
• 金额: $ 10.29万
• 依托单位: Shiga University of Medical Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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-18390100/
• 关键词: diabetic complication; bone marrow; diabetes mellitus; insulin; TNF-α; proinsulin; gene therapy

Chronic diabetic complications are the major cause of morbidity and mortality among patients with diabetes. We have reported that the fusion of proinsulin-producing (Proins-P) bone-marrow-derived cells (BMDC) with nerve cells underlies diabetic neuropathy in rodents. We also reported that diabetes in mice is associated with the appearance of Proins-P cells in the liver. It was unclear, however, whether these Proins-P BMDC merely transit through the liver or undergo fusion with hepatocytes, normally an extremely rare event. In this study, we found that, in diabetes, BMDC in the liver produce not only Proins but also TNF-a, suggesting that diabetes reprograms gene expression in BMDC, turning on "inappropriate" genes. Bone marrow transplantation using genetically marked donor and recipient mice showed that fusion occurs between Proins-P BMDC and hepatocytes. Cell fusion is further supported by the presence of the Y chromosome in Proins-P cells in female mice that received male bone marrow transplantation cells. Morphologically, Proins-P fusion cells are albumin-producing hepatocytes that constitute 〓2.5% of the liver section area 5 months after diabetes induction. An extensive search failed to reveal any fusion cells in nondiabetic mice. Thus, diabetes causes fusion between Proins-P BMDC and hepatocytes in vivo, an observation that has implications for the pathophysiology of diabetes as well as the fundamental biology of heterotypic cell fusion. To clarify the contribution of TNF-a in Proins-P BMDC on the pathogenesis of diabetic complications, we are generating gene therapeutic vector to suppress TNF-a expression by RNAi. The experiment is ongoing at present, but can show an evidence that the cell fusion have an important roles in the pathogenesis of diabetic complications.

慢性糖尿病并发症是糖尿病患者发病和死亡的主要原因。我们已经报道了产生胰岛素原（Proins-P）的骨髓源性细胞（BMDC）与神经细胞的融合是啮齿动物糖尿病神经病变的基础。我们还报道了小鼠的糖尿病与肝脏中Proins-P细胞的出现有关。然而，目前尚不清楚这些Proins-P BMDC是否仅通过肝脏转运或与肝细胞融合，这通常是非常罕见的事件。在这项研究中，我们发现，在糖尿病中，肝脏中的BMDC不仅产生Proins，而且还产生TNF-α，这表明糖尿病重新编程BMDC中的基因表达，打开“不合适”的基因。使用遗传标记的供体和受体小鼠的骨髓移植显示Proins-P BMDC和肝细胞之间发生融合。接受雄性骨髓移植细胞的雌性小鼠中Proins-P细胞中存在Y染色体进一步支持细胞融合。形态学上，Proins-P融合细胞是产生白蛋白的肝细胞，其构成糖尿病诱导后5个月的肝截面面积的约2.5%。广泛的搜索未能在非糖尿病小鼠中发现任何融合细胞。因此，糖尿病导致Proins-P BMDC和肝细胞在体内融合，这一观察结果对糖尿病的病理生理学以及异型细胞融合的基础生物学具有影响。为了阐明Proins-P BMDC中TNF-α在糖尿病并发症发病机制中的作用，我们正在制备基因治疗载体以通过RNAi抑制TNF-α表达。目前该实验尚在进行中，但可以证明细胞融合在糖尿病并发症的发病机制中具有重要作用。

项目成果

糖尿病学 2007

糖尿病学 2007

• 发表时间: 2007
• 作者: 山縣和也;堅田温子;佐藤叔史;福井健司;山縣和也;山縣和也;山縣 和也;山縣 和也
• 通讯作者: 山縣 和也

Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes

• DOI: 10.1073/pnas.0700220104
• 发表时间: 2007-03-06
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Fujimiya, Mineko;Kojima, Hideto;Chan, Lawrence
• 通讯作者: Chan, Lawrence

肝・骨髄幹細胞からの再生

肝脏/骨髓干细胞再生

• 发表时间: 2006
• 期刊: Diabetes Frontier 17
• 作者: 小島秀人;木村博;藤宮峯子;柏木厚典
• 通讯作者: 柏木厚典

Isolation of specific peptides that home to dorsal root ganglion neurons in mice

• DOI: 10.1016/j.neulet.2008.01.062
• 发表时间: 2008-04
• 期刊: Neuroscience Letters
• 影响因子: 2.5
• 作者: J. Oi;T. Terashima;Hideto Kojima;M. Fujimiya;Kengo Maeda;R. Arai;L. Chan;H. Yasuda;Atsunori Kashiwagi;H. Kimura

膵および膵外におけるNgn3とNeuroD1の発現調節と機能

胰腺和胰腺外 Ngn3 和 NeuroD1 表达和功能的调节

• 发表时间: 2008
• 期刊: 内分泌・糖尿病科 26
• 作者: 小島秀人;木村博
• 通讯作者: 木村博