T-tubule remodeling and Ca2+-dependent arrhythmogenesis in cardiomyopathies.

心肌病中的 T 管重塑和 Ca2 依赖性心律失常发生。

• 批准号: 7837390
• 负责人: Long-Sheng Song
• 金额: $ 23.26万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837390
• 关键词: Address; Animal Welfare; Arrhythmia; Arts; Bibliography; Cardiac Myocytes; Cardiomyopathies; Cause of Death; Cells; Country; Coupling; Cyclic AMP-Dependent Protein Kinases; Development; Disabled Persons; Employee Strikes; Environment; Environmental Impact; Equipment; Functional disorder; Genetic; Heart; Heart failure; Homeostasis; Human; IACUC; Image; Immunofluorescence Immunologic; Inbred SHR Rats; International; Modeling; Mus; Muscle Cells; Names; Orphan; Patients; Phosphorylation; Phosphorylation Site; Play; Principal Investigator; Publishing; Research; Research Ethics Committees; Resolution; Resource Sharing; Resources; Role; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoplasmic Reticulum; Signal Pathway; Signal Transduction; System; Techniques; Testing; Therapeutic; Up-Regulation; Vertebrates; abstracting; base; calmodulin-dependent protein kinase II; digital imaging; expiration; human subject; image processing; improved; insight; patch clamp; prevent; programs; response; seal; sudden cardiac death

Heart failure (HF), the fastest-growing type of cardiac disease in the U.S., is a pathophysiologic state in which the heart fails to pump sufficient blood to meet the needs of the body. In failing ventricular myocytes from animal models and human patients, we and others have demonstrated disruption of the widely distributed and highly organized cardiomyocyte traverse (T)-tubule system. These orderly invaginations of surface membrane into the cell interior are critical for rapid electric excitation, initiation and synchronous triggering of sarcoplasmic reticulum (SR) Ca2+ release, and, therefore, coordinated contraction of each contractile unit throughout the entire myocyte. T-tubule loss and disorganization instigate development of HF due to aberrant intracellular Ca2+ release and blunted contractile function. However, there is a limited understanding of the molecular mechanisms and pathways that regulate T-tubular integrity or that participate in destructive T-tubule remodeling. Our preliminary data indicate that junctophilin-2 (JP2), a structural protein spanning T-tubules and the SR membrane, is crucial for normal T-tubule organization. Our data in animal models of cardiac stress show that downregulation of the JP2 is associated with T-tubule disorganization and HF development. Furthermore, our preliminary results indicate that JP2 downregulation is driven by activation of the Ca2+- dependent protease, calpain, though the upstream events that result in calpain-mediated degradation of JP2 in HF remain unclear. The goal of this project is to define the mechanisms of JP2 dysregulation and T-tubule remodeling in cardiac disease. We will combine multidisciplinary approaches including in situ confocal imaging, electrophysiology, molecular biology, pathological mouse models and novel transgenic mouse models, to test two specific aims. Aim 1. To define the molecular mechanisms underlying JP2 downregulation in heart failure. Aim 2. To determine if and how recombinant JP2 expression can attenuate stress-induced T-tubule remodeling and protect against HF progression. As HF is the most common cause of hospitalization in patients over 65 and causes an enormous burden on our health care system, new therapeutic approaches for HF are still critically needed. The potential positive impact of these studies is that preventing T-tubule dysfunction may represent a novel mechanism-based approach to improve health care outcomes related to HF. Understanding these molecular mechanisms will provide a novel platform for T-tubule-targeted therapies that prevent HF development and progression.

心力衰竭（HF）是美国心脏病的增长最快的类型，是一种病理生理状态，其中心脏无法泵入足够的血液无法满足人体的需求。在动物模型和人类患者的心室肌细胞失败时，我们和其他人表现出了广泛分布和高度有组织的心肌细胞（T） - 微管系统的破坏。这些有序的表面膜进入细胞内部至关重要，对于肌浆网（SR）CA2+释放的快速电激发，起始和同步触发，因此在整个整个肌细胞中每个收缩单元的协调收缩。由于异常的细胞内Ca2+释放和收缩功能钝化，T型管损失和混乱刺激了HF的发展。然而，对调节T-管完整性或参与破坏性T型管重塑的分子机制和途径的理解有限。我们的初步数据表明，跨t-tubules的结构蛋白和SR膜的结合蛋白-2（JP2）对于正常的T型管组织至关重要。我们在心脏应力动物模型中的数据表明，JP2的下调与T型混乱和HF发育有关。此外，我们的初步结果表明JP2下调是由Ca2+依赖性蛋白酶（Calpain）的激活驱动的，尽管导致CALPAIN介导的HF中JP2降解的上游事件尚不清楚。该项目的目的是定义心脏病中JP2功能不全和T-home重塑的机制。我们将结合多学科方法，包括原位共聚焦成像，电生理学，分子生物学，病理小鼠模型和新型转基因小鼠模型，以测试两个特定的目标。目的1。定义心力衰竭中JP2下调的分子机制。目的2。确定重组JP2表达是否以及如何减轻应力诱导的T-pubule重塑并预防HF进展。由于HF是65岁以上的患者住院的最常见原因，并在我们的医疗保健系统上造成了巨大负担，因此仍然需要采用新的HF治疗方法。这些研究的潜在积极影响在于，防止T型管功能障碍可能代表了一种基于机制的新方法，以改善与HF相关的医疗保健结果。了解这些分子机制将为t-tubule靶向HF发育和进展的靶向疗法提供新的平台。