THE IMPACT OF HYPOXIA ON DEVELOPMENT AND REMODELING OF CARDIC INTERCALATED DISK

缺氧对贲门闰盘发育和重塑的影响

• 批准号: 7952469
• 负责人: David C Spray
• 金额: $ 15.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7952469
• 关键词: Acid-Base Equilibrium; Action Potentials; Acute; Affect; Affinity; Binding; Brain; Brain Hypoxia-Ischemia; Carbon Dioxide; Cardiac; Cardiac Myocytes; Cell Adhesion Molecules; Cell Death; Cell Hypoxia; Cells; Chronic; Co-Immunoprecipitations; Complex; Connexin 43; Connexins; Coupled; Data; Development; Electrons; Event; Gap Junctions; Goals; Heart; Hypercapnia; Hypoxia; Individual; Injury; Intercalated disc; Ischemia; Kidney; Literature; Mediator of activation protein; Modeling; Molecular Chaperones; Mus; Muscle Cells; Neonatal; Oxygen; Pathway interactions; Physiological; Proteins; Regulation; Research; SRC gene; Scaffolding Protein; Stimulus; Stress; Surface Plasmon Resonance; Testing; Tissues; Western Blotting; animal tissue; base; cell injury; cell killing; design; gap junction channel; heart cell; in vivo; injured; intercellular communication; interest; programs; protein-tyrosine kinase c-src; research study; response; tissue culture

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.

心脏是低氧引起的形态和生理改变的主要靶点。在急性缺血事件后，心脏缝隙连接的主要变化已被证明，包括受损细胞的功能和表达降低，以及随着组织重构，Cx43在心肌细胞中的分布重组。此外，在缺血损伤后，受损心肌细胞之间的缝隙连接的表达似乎是有害的，允许细胞死亡从受损细胞扩散到相邻的相邻细胞(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。在这项提案中要检验的一般假设是 Cx43形成的缝隙连接既是缺氧性心脏损伤的靶点，也是心肌损伤的介质。 为该项目明确提出的研究将专门研究缺血的两个组成部分：缺氧和高碳酸血症对心脏缝隙连接的影响。我们将验证三个假说：a)低氧和高二氧化碳可能通过改变Cx43及其相关蛋白的表达或改变Cx43与其结合伙伴的亲和力来影响心脏缝隙连接的发育，b)低氧和高二氧化碳将导致缝隙连接或半管的功能改变，以及c)发育中的心脏缝隙连接可以传播在应激条件下增强的细胞损伤。这些假说主要是基于我们之前对缝隙连接对相关刺激的反应的研究，在某些情况下，通过使用动物心脏组织获得的初步数据证实了这些假说 在缺氧室中1-2周。我们期望这些研究将提供有关缺血应激对缝隙连接影响的新信息。此外，由于我们对大脑和肾脏的缝隙连接以及细胞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广泛做出贡献。