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心臓の働きとその異常(3)
心疾患治療の挑戦
平成28年 5月23日
医学部薬理学講座
岡本 洋介
前にあるプリントと出席カードを一枚ずつ
取って行って下さい.
http://www.slideshare.net/Okamotoyosuke/
Global Burden of Disease(Institute for Health Metrics and Evaluation, 2013)
がん
心疾患
肺疾患
下痢,感染症
HIV,結核
心不全
心不全
? 心臓のポンプ機能が相対的に不十分な状態
? 尿量減少
? 胸水
? 下腿浮腫
? 5年生存率は約50%
? 大腸癌より予後不良
? 心不全の最大の危険因子は高血圧
? 血圧を下げるのも治療の一つ
正常の胸部X線像 心不全患者の胸部X線像
障害電流
P
Q
R
S T
心筋梗塞の心電図
ST segment
P
Q
R
S
T
障害電流
电気的除细动
心室性不整脈
(心室頻拍,心室細動)
P
Q
R
S
T
ST segment
QT interval
Q
T
R-on-T
蚕罢间隔が延长すると危険!!
蚕罢间隔が延长すると危険!!
早期後脱分極(EAD)
正常のQT
QT延長 R-on-T
Torsade de Pointes
(Twist of the point)
EpiEndoECG
EpiECG
蚕罢间隔が延长すると危険!!
Reentry !!
QT延長の原因
1. 薬剤性
2. 低K+血症
3. 家族性
QT延長の原因
1. 薬剤性
2. 低K+血症
3. 家族性(蚕罢延长症候群)
蚕罢延长症候群
遺伝子クローニング
原因遺伝子を同定したい
原因遺伝子をクローニングしたい
原因遺伝子をコピーしたい
原因遺伝子の「切り貼り」,
「複写」が可能になる
LQT1のポジショナル?クローニング
? 人のゲノムは約30億塩基対 (bp)
(このうち2%が遺伝子)
? 解析用ゲノムマーカー (Généthon
map)が約5000
? 平均すると約60万bp毎にマー
カーがある(30億÷5000 = 60万)
ヒトの染色体
心臓の働きとその异常(3)
LQT1のポジショナル?クローニング
1. 30億bpの塩基配列を全て解読するのは
たいへん!(当時は不可能だった)
2. ゲノム上のどの領域(ポジション)が遺伝
すると病気になるのか,ゲノムマーカー
を頼りに絞り込む
3. 絞り込んだ領域に対応する遺伝子を
cDNAライブラリー(遺伝子ライブラリー)
から同定する
Wang, Q. et al. Nat. Genet. 12, 17–23 (1996).
Wang, Q. et al. Nat. Genet. 12, 17–23 (1996).
電位依存性K?チャネルだった!
真核生物のセントラルドグマ
TTTT 逆転写
cDNA (complementary DNA,
相補DNA)
「Essential 生物学 第3版」
ブルガダ症候群
Nademanee, K et al.Circulation (1997)
ブルガダ症候群の心電図 (ECG)
V1, V2誘導で右室ブロック型のST上昇
ブルガダ症候群は,(ほとんどの場合)
電位依存性Na+チャネルの機能障害
電位依存性Na+チャネルのクローニング
Beneski & Catterall, Proc
Natl Acad Sci U S A (1980)
Payandeh, J., Scheuer, T., Zheng,
N. & Catterall, W. Nature (2011).
C
植え込み型除细动器
心房细动
(The Global Burden of Disease 2010, released 2013)
死亡者数の推移
(年)
健康損失者数の推移
(人)
201020001990 (年)201020001990
世界における心房细动患者数の推移
Source:
Prime minister of Japan
and his cabinet(website)
Source: Peak-Sport online
Source: trading card database
心原性脳塞栓症
(心房细动に合併する重篤な脳梗塞)
カテーテル?アブレーション
アブレーション前 アブレーション後
慶應義塾大学病ホームページ
http://kompas.hosp.keio.ac.jp/contents/000399.html
LARA
Ha?ssaguerre M, et al.
N Engl J Med. (1998) 339: 695-666. B
C
A
PV
2004年 ヒトゲノム計画
完了
はじめて全ヒトゲノムが
解読された.
(Ellinor, et al. Nat Genet 2012)
心房细动のゲノムワイド関連解析(GWAS)
ゲノムマーカーの最小単位であ
るSNP(一遺伝子多型)の位置
統計学的検定
GWASでは,それぞれのSNP(約60万ある)と
疾患との関連をχ2検定で統計学的に検定する.
統計学では帰無仮説(「このSNPは心房细动と
関係がない」という仮説)を棄却する事で,対立
仮説(「このSNPは心房细动と関係がある」)を
支持する.P値は帰無仮説を棄却することが誤
りである危険率を示す.
(Ellinor, et al. Nat Genet 2012)
心房细动のゲノムワイド関連解析(GWAS)
ゲノムマーカーの最小単位であ
るSNP(一遺伝子多型)の位置
ポストゲノム时代
Luger, et al. Nature 1997
Heterochromatin
Euchromatin
50 nm
Histone tails
ヒストンコード仮説
エピゲノムの例
?女王蜂
?マウス
?ヒト
? 食生活
? 炎症
? 喫煙
? 大気汚染
? 環境ホルモン
http://www.slideshare.net/Okamotoyosuke/

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心臓の働きとその异常(3)