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Development of the modulator drug specifically targeting biomechanical reaction in the circulatory system and the application for experimental therapeutics.

开发专门针对循环系统生物力学反应的调节药物及其在实验治疗中的应用。

基本信息

批准号：
08557139
负责人：
NAKAYAMA Koichi
金额：
$ 5.12万
依托单位：
University of Shizuoka
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

Purpose The cardiovascular response to hemodynamic/biomechanical stimuli, including pressure and flow, is a type of physical reception and a subsequent intra/inter cellular signaling in the heart and blood vessels. Pathophysiological conditions, such as vasospasm, hypertension, and myocardial hypertrophy, are also caused by the abnormal biomechanical stimuli. In order to elucidate the mechanism for mechano-transduction and to develop a new modulator of biomechanical reaction in the cardiovascular system, the following experiments were undertaken : 1) intra/intercellular signaling mechanism of arterial tissues and cells isolated from brain artery and lung in response to pressure and stretch with the special regard to protein tyrosyl phosphorylation, intracellular Ca2+ concentration, and mechanical activity. 2) Search for a new modulator of the response to hemodynamic stimuli. 3) Experimental therapeutics in the monocrotaline-induced pulmonary hypertensive rats. Results and discussions A … More s to the mechanism for mechano-transduction, the following process could be suggested : The membrane depolarization and activation of L-type Ca2+ channels through protein tyrosyl phosphorylation of the mechano-gated channel triggers the mechanical activity. Morcover, platelet-derived growth factor receptor- b chain, a receptor type of tyrosine kinase, and an intracellular messenger, such as Rho, a low molecular GTP-binding protein, are specifically involved in the signaling of mechano-transduction. Future prospect The cardiovascular response to hemodynamic stimuli touch the core of up to-date problems, including regulation of blood pressure and flow, myogenic tone, mechano-gated ion channels, shear stress and endothelial function, and pathophysiological implications of high and low shear stress and hemodynamic overload. Our present studies will surely open the way to an era for the development of new cardiovascular drugs with a novel mechanism of action, and our general principle will improve the knowledge about the cardiovascular system in health and disease. Less

目的心血管对血流动力学/生物力学刺激（包括压力和流量）的反应是心脏和血管中的一种物理接收和随后的细胞内/细胞间信号传导。病理生理状况，如血管痉挛、高血压和心肌肥大，也是由异常的生物力学刺激引起的。为了阐明机械力信号转导的机制并开发新的心血管系统生物力学反应调节剂，进行了以下实验：1）从脑动脉和肺分离的动脉组织和细胞响应压力和牵张的细胞内/细胞间信号转导机制，特别关注蛋白质酪氨酰磷酸化、细胞内Ca 2+浓度和机械活性。2)寻找对血流动力学刺激反应的新调节剂。3)野百合碱诱导肺动脉高压大鼠的实验治疗。结果和讨论A ...更多信息关于机械力信号转导的机制，我们认为：机械力门控通道的蛋白酪氨酸磷酸化导致L型钙通道的膜去极化和激活，从而触发机械力信号转导。Morcover，血小板衍生生长因子受体- B链，一种酪氨酸激酶的受体类型，和细胞内信使，如Rho，一种低分子GTP结合蛋白，特异性地参与机械转导的信号传导。未来前景心血管对血流动力学刺激的反应触及了当今问题的核心，包括血压和流量的调节、肌源性张力、机械门控离子通道、切应力和内皮功能，以及高低切应力和血流动力学超负荷的病理生理意义。我们目前的研究必将为开发具有新作用机制的新型心血管药物开辟道路，我们的一般原则将提高对健康和疾病中心血管系统的认识。少