权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

NeuroD/betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice

NeuroD/βcellulin 基因疗法诱导肝脏胰岛新生并逆转小鼠糖尿病

基本信息

批准号：
15390055
负责人：
FUJIMIYA Mineko
金额：
$ 4.54万
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：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390055/
关键词：
organogenesis panereatic β cells Helper dependent adenovirus insulin NeuroD Pdx-1 Pdx1 遺伝子治療 Pdx1、NeuroD アデノウイルスベクター膵再生骨髄ヘルパー依存型アデノウイルス Pdx-1 マウス

项目摘要

First-generation adenovirus(FGAd)-mediated transfer of the homeobox gene Pdx-1 was reported to induce hepatic insulin production and transient hypoglycemia in streptozotocin(STZ)-treated diabetic mice. Unlike FG-Ads whose effects are short-lived, helper-dependent(HD) Ads produce prolonged transgene expression. We used HDAd to deliver Pdx-1 to STZ mice and observed partial amelioration of hyperglycemia, but severe, fatal, hepatitis, caused by expression of trypsin, resulting from the exocrine-differentiating action of Pdx-1. HDAd-mediated transfer of NeuroD, a developmental factor downstream of Pdx-1,partially reversed the hyperglycemia of STZ mice without inducing hepatitis. The addition of an islet growth factor betacellulin to NeuroD completely corrected the diabetes. Treated mice were healthy and normoglycemic for the duration of the experiment (>120 days). We detected in the liver insulin and other islet-specific transcripts, including proinsulin-processing enzymes, beta cell-specific glucokinase, and sulfonylurea receptor. Immunohistochemistry revealed the presence of insulin, glucagon, pancreatic polypeptide(PP) and somatostatin-producing cells organized into islet clusters, and immuno-electron microscopy showed typical insulin-specific granules. Our data suggest that NeuroD/betacellulin is a promising gene therapy regimen for the treatment of insulin-dependent diabetes. These results were published in Nat. Med 9,596,2003 and many review articles as shown in the publication records.

据报道，第一代腺病毒（FGAd）介导的同源框基因 Pdx-1 的转移可诱导链脲佐菌素（STZ）治疗的糖尿病小鼠肝胰岛素产生和短暂低血糖。与效果短暂的 FG-Ad 不同，辅助依赖性 (HD) Ad 可以产生延长的转基因表达。我们使用 HDAd 将 Pdx-1 递送至 STZ 小鼠，观察到高血糖得到部分改善，但由于 Pdx-1 的外分泌分化作用，胰蛋白酶的表达引起了严重、致命的肝炎。 HDAd 介导的 NeuroD（Pdx-1 下游的发育因子）的转移部分逆转了 STZ 小鼠的高血糖，而不诱发肝炎。在 NeuroD 中添加胰岛生长因子 betacellulin 可以完全纠正糖尿病。在实验期间（>120 天），接受治疗的小鼠健康且血糖正常。我们在肝脏中检测到胰岛素和其他胰岛特异性转录物，包括胰岛素原加工酶、β细胞特异性葡萄糖激酶和磺酰脲受体。免疫组织化学显示存在组织成胰岛簇的胰岛素、胰高血糖素、胰多肽（PP）和生长抑素产生细胞，免疫电镜显示典型的胰岛素特异性颗粒。我们的数据表明 NeuroD/betacellulin 是一种有前途的治疗胰岛素依赖型糖尿病的基因治疗方案。这些结果发表在《Nat》上。 Med 9,596,2003 以及出版记录中显示的许多评论文章。