| Project/Area Number |
15390055
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General anatomy (including Histology/Embryology)
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
FUJIMIYA Mineko Shiga Univ.Med.Sci., Dept.Anatomy, Associate Professor, 医学部, 助教授 (10199359)
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| Co-Investigator(Kenkyū-buntansha) |
KOJIMA Hideto Shiga Univ.Med.Sci., Dept.Molecular Genetics in Medicine, Associate Professor, 医学部, 助教授 (00225434)
NAKAMURA Takaaki Shiga Univ.Med.Sci., Dept.Anatomy, Assistant Professor, 医学部, 助手 (30314157)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 2004: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2003: ¥3,700,000 (Direct Cost: ¥3,700,000)
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| Keywords | 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 |
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| Research Abstract |
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.
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