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）是美国增长最快的心脏病类型，是一种病理生理状态，其中心脏不能泵出足够的血液以满足身体的需要。在动物模型和人类患者的衰竭心室肌细胞中，我们和其他人已经证明了广泛分布和高度组织化的心肌细胞横（T）小管系统的破坏。这些有序的内陷的表面膜进入细胞内部的快速电刺激，启动和同步触发肌浆网（SR）的Ca 2+释放，并因此，协调收缩的每个收缩单位在整个肌细胞是至关重要的。由于细胞内Ca 2+释放异常和收缩功能减弱，T-小管丢失和解体引发HF的发展。然而，有一个有限的了解的分子机制和途径，调节T-小管的完整性或参与破坏性T-小管重塑。我们的初步数据表明，junctophilin-2（JP 2），一种跨越T-小管和SR膜的结构蛋白，对正常的T-小管组织至关重要。我们在心脏应激动物模型中的数据表明，JP 2的下调与T-小管紊乱和HF的发展有关。此外，我们的初步结果表明，JP 2下调是由激活的钙依赖性蛋白酶，钙蛋白酶，虽然上游事件，导致钙蛋白酶介导的降解JP 2在HF仍不清楚。本项目的目标是确定心脏疾病中JP 2失调和T-小管重塑的机制。我们将结合联合收割机多学科的方法，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。目标1。明确心力衰竭中JP 2下调的分子机制。目标2.确定重组JP 2表达是否以及如何减轻应激诱导的T-小管重塑并防止HF进展。由于HF是65岁以上患者住院的最常见原因，并给我们的医疗保健系统造成巨大负担，因此仍然迫切需要新的HF治疗方法。这些研究的潜在积极影响是，预防T管功能障碍可能代表了一种基于机制的新方法，可改善与HF相关的医疗保健结果。了解这些分子机制将为预防HF发展和进展的T-小管靶向治疗提供新的平台。