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

基本信息

批准号：
7659695
负责人：
David C Spray
金额：
$ 17.31万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7659695
关键词：
Acid-Base Equilibrium Acids Action Potentials Acute Adult Affect Affinity American Antibodies Astrocytes Binding Biology Brain Brain Hypoxia-Ischemia Carbon Dioxide Cardiac Cardiac Myocytes Cell Adhesion Molecules Cell Death Cell Hypoxia Cells Chronic Co-Immunoprecipitations Collaborations Complementary DNA Complex Condition Connexin 43 Connexins Coupled Cultured Cells Data Depth Development Electrons Electrophysiology (science)Evaluation Event Fluorescence Resonance Energy Transfer Gap Junctions Gastric Glands Goals Heart Human Resources Hypercapnia Hypoxia Individual Injury Intercalated disc Ischemia Kidney Literature Localized Mediator of activation protein Methods Modeling Molecular Chaperones Mus Muscle Cells Neonatal Neurons Oligonucleotide Microarrays Organization and Administration Oxygen Pathway interactions Physiological Protein Binding Proteins Publications Purinoceptor Reagent Regulation Research Research Personnel Role SRC gene San Francisco Scaffolding Protein Signal Transduction Stimulus Stress Surface Plasmon Resonance Testing Tissues VDAC1 gene Ventricular Week Western Blotting Work animal tissue base brain tissue cell injury cell killing design heart cell hypoxia neonatorum in vivo injured intercellular communication interest programs protein-tyrosine kinase c-src research study response tissue culture water channel

项目摘要

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.

心脏代表了缺氧引起的形态学和生理改变的主要靶标。急性缺血事件发生后，已经证明了心脏间隙连接的重大变化，包括损害细胞的功能和表达降低以及心脏肌肉细胞中CX43分布作为组织重塑的重组。此外，受伤的肌细胞之间的间隙连接在缺血性损伤后似乎是有害的，从而使细胞死亡从受伤的细胞传播到耦合的邻居（这种现象称为“旁观者细胞死亡”）；非协同的半通道开口也可能导致这种细胞死亡。在此提案中要检验的一般假设是 CX43形成的间隙连接是缺氧引起的心脏损伤的靶标和介体。明确提出的针对该项目的研究将特别研究对缺血的两个组成部分的心脏间隙连接的影响：缺氧和高碳酸盐。我们将检验三个假设：a）缺氧和高碳酸血症可能会通过改变CX43及其相关蛋白的表达及其相关蛋白的表达或CX43对其结合伴侣的亲密性的改变，b）缺氧和高碳酸盐会在GAP连接或半细胞增强的情况下产生gap indection coption coption copt copt copt copt copt copt copt copt copt copt copt coption coption coptions off in gyap inde coptions off in gyap，b）cx43对其结合伴侣的结合伴侣的影响。这些假设主要是基于我们先前对间隙连接对相关刺激的反应的研究，在某些情况下通过使用心脏组织获得的动物的初步数据证实在缺氧腔室中1-2周。我们预计这些研究将提供有关对缺血相关应力差距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调节的基本机制的兴趣，我们将从该计划的其他项目中受益并广泛贡献。