2003 Fiscal Year Final Research Report Summary
Analysis of gene therapy and its effect to hypothalamic-pituitary-adrenal axis
| Project/Area Number |
14570711
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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 |
Pediatrics
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
TAJIMA Toshihiro Hokkaido Univ., Grad.School of Med., Inst., 大学院・医学研究科, 助手 (50333597)
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| Co-Investigator(Kenkyū-buntansha) |
OKADA Tadashi Jichi Medi School., Inst., 医学部, 助手 (00326828)
ARIGA Tadashi Hokkaido Univ., Grad.School of Med., Corporate Donated Chair Teacher., 大学院・医学研究科, 寄附講座教員 (60322806)
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| Project Period (FY) |
2002 – 2003
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| Keywords | CAH / Gene therapy / Adenovirus vector / Hypothalamus / Pituitary |
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| Research Abstract |
We studied the feasibility of gene therapy was studied using 21-OH deficient mice and a replication-deficient adenovirus system. Intra-adrenal injection of adenovirus-human 21-OH gene vector induced mRNA with highest expression from 2 to 7 days before a gradual decline. After injection, plasma corticosterone level did not significantly after 4days, but increased to similar level to these in wild type mice by 7,14, and 30 days. Adrenal morphology of 21-OH deficient mice showed lack of zonation, and hypertrophy and hyperplasia of adrenocortical mitochondria with few tubulovesicular christae. These morphological abnormalities were markedly improved 7 days after gene delivery. Plasma corticosterone increased from undetectable level to values similar in wild type mice by 7 and 14 days, declining over the next 40 days.
To determine whether hypothalamic-pituitary axis was normalized by gene delivery and subsequent increase of corticosterone, mRNA levels of POMC in pituitary was analyzed by in situ hybridization. As results, mRNA levels of POMC was not suppressed after gene delivery. Reflecting this, serum progesterone, that is precursor steroid of corticosterone remained high after gene delivery. These findings indicate that more stable induction of 21-hydroxylase activity may be required to normalize hypothalamic-pituitary axis in 21-OH deficient mice.
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