THE IMPACT OF HYPOXIA ON DEVELOPMENT AND REMODELING

缺氧对发育和重塑的影响

• 批准号: 6910146
• 负责人: David Spray
• 金额: $ 16.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-17 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6910146
• 关键词: cadherins; cardiovascular injury; gap junctions; growth /development; heat shock proteins; hypercapnia; hypoxia; immunoprecipitation; laboratory mouse; muscle cells; myocardium; protein binding; protein protein interaction; protein tyrosine kinase; western blottings

The heart represents a primary target of hypoxia-induced morphological and physiological alterations. Major alterations in cardiac gap junctions have been demonstrated following acute ischemic events, including decreased function and expression in damaged cells as well as reorganization of Cx43 distribution in the cardiac muscle cells as the tissue remodels. Moreover, expression of gap junctions between injured myocytes appears to be deleterious following ischemic injury, allowing spread of cell death from the injured cell to coupled neighbors (a phenomenon termed "bystander cell death"); nonjunctional hemichannel opening may also contribute to this cell death. The general hypotheses to be tested in this proposal are that gap junctions formed by Cx43 are both targets and mediators of hypoxia-induced cardiac injury. The studies that are explicitly proposed for this Project will specifically study effects on cardiac gap junctions of two components of ischemia: hypoxia and hypercapnia. We will test three hypotheses: a) that hypoxia and hypercapnia may affect developing cardiac gap junctions through altered expression of Cx43 and its associated proteins or altered affinity of Cx43 for its binding partners, b) that hypoxia and hypercapnia will produce functional changes in gap junctions or hemichannels, and c) that gap junctions in developing heart can spread cell injury that is enhanced under stressful conditions. These hypotheses are formulated primarily on the basis of our previous studies of responses of gap junctions to related stimuli, substantiated in some cases by preliminary data obtained using cardiac tissue from animals maintained for 1-2 weeks in the hypoxia chambers. We expect that these studies will provide new information regarding effects on gap junctions of ischemia-related stresses. In addition, we will both benefit from and contribute broadly to the other Projects in the Program, due to our interest in gap junctions in brain and kidney and in the basic mechanisms of cellular pH regulation.

心脏是缺氧引起的形态和生理变化的主要目标。急性缺血事件后，心脏间隙连接发生了重大变化，包括受损细胞的功能和表达下降，以及组织重塑时心肌细胞中 Cx43 分布的重组。此外，缺血性损伤后，受损心肌细胞之间间隙连接的表达似乎是有害的，导致细胞死亡从受损细胞扩散到相邻的细胞（这种现象称为“旁观者细胞死亡”）；非连接半通道开放也可能导致这种细胞死亡。本提案要检验的一般假设是 Cx43 形成的间隙连接既是缺氧引起的心脏损伤的靶点也是介质。 本项目明确提出的研究将专门研究缺血的两种成分（缺氧和高碳酸血症）对心脏间隙连接的影响。我们将测试三个假设：a) 缺氧和高碳酸血症可能通过改变 Cx43 及其相关蛋白的表达或改变 Cx43 与其结合伴侣的亲和力来影响发育中的心脏间隙连接，b) 缺氧和高碳酸血症将产生间隙连接的功能变化或半通道，c）发育中的心脏中的间隙连接可以传播细胞损伤，这种损伤在压力条件下会增强。这些假设主要是根据我们之前对间隙连接对相关刺激的反应的研究提出的，在某些情况下通过使用来自维持了一定时间的动物的心脏组织获得的初步数据得到证实。 在缺氧室中 1-2 周。我们期望这些研究将提供有关缺血相关应激对间隙连接的影响的新信息。此外，由于我们对大脑和肾脏的间隙连接以及细胞 pH 调节的基本机制感兴趣，我们将从该计划的其他项目中受益并做出广泛贡献。