Analysis of biological function of tenascin-C in progression of heart failure and its clinical application

Tenascin-C在心力衰竭进展中的生物学功能分析及其临床应用

• 批准号: 10670644
• 负责人: IMAI Hiroshi
• 金额: $ 2.43万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670644/
• 关键词: Extracellular matrix; tenascin; myofibroblast; knockout mouse; myocardial infarction; myocarditis; 筋繊維芽細胞; 心疾患

In order to study the biological function, recombinant protein of tenascin-C was added to the cell cultures.1) Tenascin-C, collaborating with fibronectin, accelerates the initial attachment of cardiomyocytes isolated from adult rat to laminin, however, tenascin-C is not involved in the formation of costameric attachment. 2) Tenascin-C induces the differentiation of fibroblasts to myofibroblasts. Secondary, to clarify the role of tenascin-C if myocardial tissue in vivo, we examined the wound healing of a mouse myocardial infarction model using tenascin-C knockout mouse. In tenascin-C null mutant, the number of smooth-muscle actin-positive cells was delayed to compare to that of normal mouse, however, healing proceeded normally. Tenascin-X, another member of tenascin family was ubiquitously expressed in normal heart, and slightly unregulated after myocardial injury at later stage. Our findings did not suggested that tenascin-X compensates for the loss of tenascin-C. Finally, to examine the possibility of the clinical application anti tenascin-C, we have established a new autoimmune mouse model. We also raised a mouse monoclonal antibody, which recognizes mouse tenascin-C by immunization of a tenascin-C knock out mouse. Immunoshitological study showed that tenascin-C expressed at very early stage of active phase of myocarditis. Our data demonstrate that tenascin-C is a useful marker for histological diagnosis to evaluate disease activity of myocarditis.

为了研究其生物学功能，将tenascin-C的重组蛋白添加到细胞培养物中。1) Tenascin-C与纤连蛋白协同作用，加速成年大鼠分离的心肌细胞与层粘连蛋白的初始附着，然而，tenascin-C是不参与肋节附着的形成。 2) Tenascin-C诱导成纤维细胞分化为肌成纤维细胞。其次，为了阐明生腱蛋白-C 在体内心肌组织中的作用，我们使用生腱蛋白-C 敲除小鼠检查了小鼠心肌梗死模型的伤口愈合情况。在生腱蛋白-C无效突变体中，与正常小鼠相比，平滑肌肌动蛋白阳性细胞的数量延迟，但愈合过程正常进行。 Tenascin-X是腱蛋白家族的另一成员，在正常心脏中广泛表达，在心肌损伤后期稍微不受调节。我们的研究结果并未表明生腱蛋白-X 可以补偿生腱蛋白-C 的损失。最后，为了检验抗生腱蛋白-C临床应用的可能性，我们建立了一种新的自身免疫小鼠模型。我们还制备了一种小鼠单克隆抗体，它通过免疫腱蛋白-C 敲除小鼠来识别小鼠腱蛋白-C。免疫组织学研究表明，tenascin-C在心肌炎活动期的早期阶段表达。我们的数据表明生腱蛋白-C 是组织学诊断评估心肌炎疾病活动性的有用标记物。

项目成果

Imanaka-Yoshida, K., et al.: "Futura, New York"Possible roles of the tenascin family in the early heart development. In : Clark EB, Nakazawa M, and Takao A(eds) "The Heart Development" eds : Takao Nakazawa M. (in press).

Imanaka-Yoshida, K. 等人：“Futura，纽约”腱蛋白家族在早期心脏发育中的可能作用。

Imanaka-Yoshida,K.,et al.: "alpha6betal and laminin can serve as components of attachment complex mediating contraction force transmission from cardiomyocytes to extracellular matrix"Cell Motil Cytoskeleton. 42. 1-11 (1999)

Imanaka-Yoshida，K.，等人：“α6β1 和层粘连蛋白可以作为附着复合物的成分，介导从心肌细胞到细胞外基质的收缩力传递”Cell Motil 细胞骨架。

M,Takahashi.et al.: "Role of microtubules in the contractile dysfunction of myocytes from tachycardia-induced dilated cardiomyopathy." J.Mol.Cell.Cardiol.30. 1047-1057 (1998)

M，Takahashi.et al.：“微管在心动过速引起的扩张型心肌病心肌细胞收缩功能障碍中的作用。”

Imanaka-Yoshida, K., et al.: "Vinculin, Talin, Integrin alpha6betal and laminin can serve as components of attachment complex mediating contraction force transmission from cardiomyocytes to extracellular matrix"Cell Motil Cytoskeleton. 42. 1-11 (1999)

Imanaka-Yoshida, K. 等人：“Vinculin、Talin、整合素 α6β1 和层粘连蛋白可以作为附着复合物的成分，介导从心肌细胞到细胞外基质的收缩力传递”Cell Motil 细胞骨架。

Imanaka-Yoshida, K., et al.: "N-cadherin is required for the differentiation and initial myofibrillogenesis of chick cardiomyocytes"Cell Motil Cytoskeleton. 39. 52-62 (1998)

Imanaka-Yoshida, K. 等人：“鸡心肌细胞的分化和初始肌原纤维形成需要 N-钙粘蛋白”Cell Motil Cytosculpture。