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Molecular anatomical research for the role of gap junction proteins in cardiac function.

间隙连接蛋白在心脏功能中作用的分子解剖学研究。

基本信息

批准号：
17390052
负责人：
SHIBATA Yosaburo
金额：
$ 8.9万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390052/
关键词：
gap junction connexin knockout mouse cardiac development endocardial cushion heart gap junction connexin gene targeting NFATc1 endocardial cushion atrioventricular block

项目摘要

Among gap junction protein connexins, we focused on the function of connexin43 (Cx43) and connexin45 (Cx45) that are the major connexins in cardiac system. First, we analyzed the early myocardial contraction and the cardiac development using Cx43 and Cx45 deficient mice (Cx43-KO and Cx45-KO). We found intriguing differences of phenotypes between two KO mice. Cx43-KO died just after birth but showed coordinated myocardial contraction and formed endocardial cushion. In contrast, Cx45-KO showed initiation of myocardial contraction and partial coordination of contraction at E.8.25 stage, but died within next 24 hours by the atrioventricular contraction block and by the defect in the formation of endocardial cushion. Second, we made conditional KO mice lacking the Cx45 expression specifically in vascular endothelial cells (Cx45-Tie2) and cardiac myocytes (Cx45-CA) respectively, because Cx45 is mainly expressed in these cells. Cx45-CA was lethal due to an atrioventricular contraction block s … More imilar to Cx45-KO though the endocardial cushion was formed. Furthermore, Cx43/45 double KO showed the same phenotype as Cx45-KO. These data suggest the functions of Cx43 and Cx45 in the initiation of myocardial contraction and the formation of endocardial cushion as following. (1) Cx43 is scarcely involved in these processes. (2) Lacking Cx45 in myocardial cells induces contraction block. (3) Lacking Cx45 both in myocardial cells and endocardial endothelial cells induces defect in the formation of endocardial cushion.In addition to these results, the deficiency in the formation of endocardial cushion varied in Cx45-CA mice, suggesting that soluble factor derived from Cx45 expressing cells in heart is essential for these processes. We proposed the new model ; Activation of Ca^<2+> dependent transcription factor NFATc1, which is involved in valve induction in heart development, is critical for the formation of endocardial cushion. In this model, Ca^<2+> wave propagates by passing through Cx45 containing gap junctions and triggers the synchronized activation of Ca^<2+>/calcineurin/NFATc1 system.Cx45-KO showed moderately coordinated contraction until lethal stage. This suggests another gap junction protein, pannexin that is a vertebrate homologue of innexin for example, might be involved in the formation of the functional gap junction at early stages of cardiac development. This should be addressed afterwards. Less

在缝隙连接蛋白中，我们重点研究了心脏系统中主要的连接蛋白连接蛋白43（Cx43）和连接蛋白45（Cx45）的功能。首先，我们使用Cx43和Cx45缺陷小鼠（Cx43-KO和Cx45-KO）分析了早期心肌收缩和心脏发育。我们发现两个KO小鼠之间的表型有趣的差异。Cx43-KO在出生后即死亡，但表现出协调的心肌收缩并形成内膜垫。相反，Cx45-KO在E.8.25期显示心肌收缩的开始和收缩的部分协调，但在接下来的24小时内由于房室收缩阻滞和内膜垫形成缺陷而死亡。第二，我们制作了分别在血管内皮细胞（Cx45-Tie 2）和心肌细胞（Cx45-CA）中特异性缺乏Cx45表达的条件性KO小鼠，因为Cx45主要在这些细胞中表达。Cx45-CA由于房室收缩阻滞而致死。 ...更多信息与Cx45-KO相似，但形成了内膜垫。此外，Cx43/45双KO显示与Cx45-KO相同的表型。提示Cx43和Cx45在心肌收缩起始和内膜垫形成中的作用。(1)Cx43几乎不参与这些过程。(2)心肌细胞中缺乏Cx45会导致收缩阻滞。(3)Cx45-CA小鼠心肌细胞和内皮细胞Cx45的缺失导致了内皮细胞垫形成的缺陷，此外，Cx45-CA小鼠的内皮细胞垫形成的缺陷也不同，提示心脏Cx45表达细胞来源的可溶性因子在这些过程中是必不可少的。我们提出了一个新的模型：在心脏发育过程中参与瓣膜诱导的Ca^<2+>依赖性转录因子NFATc 1的激活对内膜垫的形成至关重要。在该模型中，Ca^2+波通过含有缝隙连接的Cx45进行传播，并触发Ca^2+/calcineurin/NFATc 1系统的同步激活，Cx45-KO表现出中度协调收缩直至致死阶段。这表明另一种间隙连接蛋白，例如作为innexin的脊椎动物同源物的泛连接蛋白，可能参与心脏发育早期功能性间隙连接的形成。这一问题应在以后解决。少

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Heterogeneity in expression and subcellular localization of tight junction proteins, claudin-10 and-15, examined by RT-PCR and immunofluorescence microscopy

DOI：
10.1679/aohc.68.349
发表时间：
2005-12-01
期刊：
ARCHIVES OF HISTOLOGY AND CYTOLOGY
影响因子：
0
作者：
Inai, T;Sengoku, A;Shibata, Y
通讯作者：
Shibata, Y

Identification of heat shock protein Hsp40/DjB1 as an acrosome- and a tail-associated component in rodent spermatozoa.

鉴定热休克蛋白 Hsp40/DjB1 作为啮齿动物精子顶体和尾部相关成分。

DOI：
发表时间：
2007
期刊：
Mol.Reprod.Dev. 74(2)
影响因子：
0
作者：
M.Doiguchi;T.Kaneko;A.Urasoko;H.Nishitani;H.Iida
通讯作者：
H.Iida

Segment-specific expression of tight junction proteins, claudin-2 and-10, in the rat epididymal epithelium

DOI：
10.1679/aohc.68.213
发表时间：
2005-09-01
期刊：
ARCHIVES OF HISTOLOGY AND CYTOLOGY
影响因子：
0
作者：
Guan, X;Inai, T;Shibata, Y
通讯作者：
Shibata, Y

Molecular cloning of rat Spetex2 family genes mapped on chromosome 15p16, encoding a 23-kilodalton protein associated with the plasma membranes of haploid spermatids.

定位在染色体 15p16 上的大鼠 Spetex2 家族基因的分子克隆，编码与单倍体精子细胞质膜相关的 23 千道尔顿蛋白质。

DOI：
发表时间：
2005
期刊：
Biol.Reprod. 72(2)
影响因子：
0
作者：
H.Iida;Y.Honnda;T.Matsuyama;Y.Shibata;T.Inai;H.Iida et al.;E.Hirose et al.;K.Nishii et al.;T.Inai et al.;X.Guan et al.;Y.Iwamoto et al.
通讯作者：
Y.Iwamoto et al.

Loss of RanGEF/Pim1 activity abolishes the orchestration of Ran-mediated mitotic cellular events in S-pombe