| Project/Area Number |
10671243
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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 |
Thoracic surgery
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
ITO Hiroshi 2nd Department of Medicine Tokyo Medical and Dental University Assistant Professor, 医学部, 助手 (10232464)
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| Co-Investigator(Kenkyū-buntansha) |
HIROE Michiaki 2nd Department of Medicine Tokyo Medical and Dental University Lecturer, 医学部, 講師 (80101872)
WATANABE Masazumi Department of Thoracic Surgery Tokyo Medical and Dental University Assistant Professor, 医学部, 助手 (10282758)
TANAKA Hiroyuki Department of Thoracic Surgery Tokyo Medical and Dental University Lecturer, 医学部, 講師 (70197466)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1998: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Keywords | Hypertrophy / Cardiomyocytes / gene therapy / adenovirus / P16 / Cre-loxP system |
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| Research Abstract |
We have succeeded to construct the cardiac muscle specific adenovirus system using Cre-lozP. We used myosin heavy chain promoter for the cardiac specific induction of Cre recombinase. Using this system, we succeeded to express LacZ protein in only cardiac muscle cells but not in fibroblasts.
In the present study, we also introduce adenovirus containing coding sequences for p16 and found that the overexpression of p16 suppress left-ventricular (LV) hypertrophy in vivo induced by aortic banding (AOB) in rats. Adenovirus vectors carrying cDNA for p16 (4.2x109 pfu) or LacZ (4.0x109 pfu) were transduced into the heart by the method reported by Hajjar et al (PNAS, 1998). By this approach, p16 or LacZ was overexpressed in the whole left ventricle as evaluated by Western blot or histochemical analysis. LV overload was produced by coarctation of ascending aorta immediately after the transduction of adenoviruses. Systolic pressure gradient between LV and descending aorta was approximately 30 mmHg in the AOB+LacZ group, and p16 did not affect the pressure gradient. Two weeks after surgery, the heart weight/body weight ratio (HW/BW) increased in AOB+LacZ group compared with the control, and p16 significantly inhibited the hypertrophy (Table). Histological analysis revealed that p16 inhibited both hypertrophy of cardiomyocytes and interstitial fibrosis in the LV wall. These results indicate that a possibility of gene therapy of cardiac hypertrophy by adenovirus systems.
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