2003 Fiscal Year Final Research Report Summary
Development of gene therapy for treatment of dilated cardiomyopathy and associated heart failure
| Project/Area Number |
14370228
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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 |
Circulatory organs internal medicine
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| Research Institution | Yamaguchi University |
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Principal Investigator |
MATSUZAKI Masunori Yamaguchi University, School of Medicine, Professor, 医学部, 教授 (60116754)
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| Co-Investigator(Kenkyū-buntansha) |
AOKI Hiroki Yamaguchi University, School of Medicine, Associate Professor, 医学部, 客員助教授 (60322244)
YANO Masafumi Yamaguchi University, Hospital, Assistant Professor, 医学部附属病院, 講師 (90294628)
IKEDA Yasuhiro Yamaguchi University, School of Medicine, Research Associate, 医学部, 寄附講座教員 (00260349)
OHKUSA Tomoko Yamaguchi University, School of Medicine, Research Associate, 医学部, 助手 (00294629)
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| Project Period (FY) |
2002 – 2003
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| Keywords | chronic hears failure / dilated cardiomyopathy / protein phosphatase 1 / Adenovirus vector / Aden associated virus vector / cardiomyopathic hamster / High efficiency in vivo cardiac gene transfer |
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| Research Abstract |
Although increase in protein phosphatase (PP) 1 activity is proposed as a detrimental mechanism together with impairment of protein kinase A (PKA) activity in several models of heart failure, it remains to be determined 1) whether this PP1 over-activity hypothesis is applicable in genetic models of cardiomyopathy (CM) and 2) if selective inhibition of PP1 can affect heart failure progression. We characterized time course of PP and PKA activity in progression of UMX7.1 hamster cardiomyopathy and investigated the effect of PP1 inhibition by inhibitor -2 (I-2), an endogenous specific inhibitor of PP1 using in vivo high efficiency cardiac gene delivery system as we previously described. We found that 1) increase in PP1 activity precedes severe LV dysfunction but does not accompany impaired PKA activity in the hamster cardiomyopathy and 2) PP1 inhibition is beneficial for preventing progressive LV dysfunction by modifying excessive β-adrenergic stimulation and can be a potential target for treatment of genetic cardiomyopathy and associated heart failure. In vivo cards ac gene transfer of dominant negative phospholamban mutant also prevented progression of post infarction heart failure in rat. There data suggest that genetic modification of Ca2+ regulatory gene by somatic gene transfer alleviate progression of heart fail ure, thus it may be applicable in the clinical settings
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[Publications] Iwanaga Y, Hoshijima Y, Gu Y, Iwatate M, Dieterle T, Ikeda Y, Date M, Chrast J, Mat suzaki M, Peterson KL, Chien KR, Ross JJr: "Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats"J Clin Invest. 113. 727-736 (2004)
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[Publications] Hoshijima M*, Ikeda Y*., Iwanaga Y., Minamisawa S., Li M., Gu Y., Wang L, Wilson J.M., Wang Y., Ross J.Jr., Chien K.R.: "Chronic Heart Failure Therapy via Cardiotropic rAAV Delivery of an S16E Mutant Phospholamban. * Co-first author"Nat Med. 8. 864-871 (2002)
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[Publications] Ikeda Y., Gu Y, Iwanaga Y., Hoshijima M, Oh S.S., Giordano F.J., Chen J, Nigro V, Peterson K.L., Chien K.R., Ross J.Jr.: "Restoration of deficient membrane protein in the cardiomyopathic hamster by in vivo cardiac gene transfer"Circulation. 105. 502-508 (2002)
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[Publications] Yano M, Kobayashi S, Kohno M, Doi M, Tokuhisa T, Okuda S, Suetsugu M, Hisaoka T, Obayashi M, Ohkusa T, Kohno M, Matsuzaki M.: "FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure"Circulation. 107(3). 477-484 (2003)
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