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KAKEN_24390201seika.pdf
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Title |
Title |
心臓拡張機能制御の解明および生体内拡張機能可視化の確立
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Kana |
シンゾウ カクチョウ キノウ セイギョ ノ カイメイ オヨビ セイタイナイ カクチョウ キノウ カシカ ノ カクリツ
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Shinzo kakucho kino seigyo no kaimei oyobi seitainai kakucho kino kashika no kakuritsu
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Diastolic dysfunction caused by titin mutation
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牧野, 伸司
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マキノ, シンジ
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Makino, Shinji
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慶應義塾大学・医学部・特任准教授
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Research team head
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科研費研究者番号 : 20306707
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山岸, 敬幸
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ヤマギシ, ヒロユキ
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Yamagishi, Hiroyuki
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慶應義塾大学・医学部・准教授
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Research team member
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科研費研究者番号 : 40255500
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有村, 卓朗
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アリムラ, タクロウ
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Arimura, Takuro
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東京医科歯科大学・難治疾患研究所・助教
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Research team member
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科研費研究者番号 : 50342887
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2016
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科学研究費補助金研究成果報告書
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2015
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Abstract |
拡張不全の予後を改善する治療方法はない。我々はメダカ変異体スクリーニングから, 心臓拡張機能異常を示す突然変異体を樹立した。ポジショナルクローニング法により, メダカ変異体はTitin遺伝子(TTN)に点変異があることを発見した。変異部位はMuscle Ring Finger(MURF)結合部位であった。メダカ変異体ではTTNとMURF結合増強により, 柔軟なTTN isoformのユビキチン化による分解で, 固いTTN isoformへの変化が観察された。メダカ拡張不全変異体と拡張不全を示す家族性心筋症のを用いて, TTNとMURF結合・解離による拡張不全発症の機序解明を行った。
Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction. We generated a cardiovascular-mutant medaka fish non-spring heart (nsh), which showed diastolic dysfunction and hypertrophic myocardium. The nsh had expressed pathologically stiffer titin isoforms. The nsh heterozygotes showed M-line disassembly. Positional cloning revealed a missense mutation in an immunoglobulin domain located in the M-line-A-band transition zone of titin. Screening of mutations in 96 unrelated patients with familial HCM, who had no previously implicated mutations in known sarcomeric gene candidates, identified two mutations in Ig domains close to the M-line region of titin. The mutations found in both medaka fish and in familial HCM increased binding of titin to MURF1 and enhanced titin degradation by ubiquitination. These findings implicate an impaired interaction between titin and MURF1 as a novel mechanism underlying the pathogenesis of HCM.
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研究種目 : 基盤研究(B)(一般)
研究期間 : 2012~2015
課題番号 : 24390201
研究分野 : 循環器内科
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