| Project/Area Number |
15590774
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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 |
Circulatory organs internal medicine
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| Research Institution | Nippon Medical School |
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Principal Investigator |
SEINO Yoshuhiko Nippon Medical School, Department of Medicine, Professor, 医学部, 教授 (10163073)
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| Co-Investigator(Kenkyū-buntansha) |
FUKUMOTO Hiroko Nippon Medical School, Department of Medicine, Research Associate, 医学部, 助手 (80339423)
HIRAI Yukihiko Nippon Medical School, Department of Medicine, Assistant Professor, 医学部, 講師 (10089617)
SHIMADA Takashi Nippon Medical School, Graduate School of Medicine, Professor, 大学院・医学研究科, 教授 (20125074)
TAKANO Teruo Nippon Medical School, Graduate School of Medicine, Professor, 大学院・医学研究科, 教授 (40133441)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2005: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | Fabry disease / gene transfer therapy / cardiac hypertrophy / NT-pro BNP / troponin T / H-FABP / ongoing myocardial damage / heart failure / atrial-ventricular block / renal failure / BNP / adriamycin cardiomyopathy / cardiac hypertriphy / Fas / Fas Ligand system / apoptosis / heart-type fatty acid binding protein / myocardial damage / enzyme replacement therapy / α-galactosidase / adeno-associated virus / N-terminal pro-brain natriuretic peptide |
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| Research Abstract |
Fabry disease is an inherited lysosomal storage disorder characterized by a pathological intracellular glycosphingolipid deposition. The disease is caused by a deficit in the lysosomal enzyme α-galatosidase A, the gene for which is located in the X chrosomal region Xq 22. Globotriaosylceramide (Gb3) accumulate progressively in multi-organ vulnerable cells throughout the body, including cardiovascular, renal, and cerebrovascular systems. Novel therapeutic strategies for this disease have been developing in recent years, which include the clinically introduced enzyme infusion replacement therapy and experimentally developing gene-transfer therapy.
1.We have developed novel AAV-mediated muscle-directed gene transfer therapy for Fabry mouse which is very effective for long-term systemic delivery of α-gal A (25% of normal mice enzyme activity), resulting in complete clearance of multi-organs Gb3 accumulation.
2.Regarding the cardiovascular system, echocardiographic and immunohistochemical exa
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minations demonstrated structural and functional suppression of the development of cardiac hypertrophy. However in the Fabry mouse mode, accumulation of Gb3 which should play an important role in the pathophysiology in clinical condition role was hardly detected, that might be one of limitation in this experimental study.
3.Advances in the understanding of the pathogenesis and consequences of ischemic heart disease or heart failure have stimulated development of novel biomarkers, and expanded their role in the different spectrum of the underlying pathophysiology. We have constructed multi-biomarker strategy ; consisted of biomarkers for 1)myocardial necrosis (membrane damage to myofibril necrosis ; H-FABP and troponin T), 2)coronary plaque destabilization, 3)myocardial stress (end-diastolic ventricular wall stress ; BNP and NT-proBNP). These strategies would be clinically useful for the early detection and therapeutic assessment in the Fabry disease managements.
4.For the future diagnostic and therapeutic assessments, we have developed cardiomyopathy model using adriamycin cardiotoxicity as the substitute, and assessed echocardiographic and biomarkers utilities.
As the summary of the present study series, we have written a review on cardiovascular and renal manifestations of Fabry disease and the new diagnostic procedures, and the novel therapeutic strategies including the clinically introduced enzyme infusion replacement therapy and experimentally developing gene-transfer therapy. Less
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