In-vivo Imaging of Calcium in the Heart

心脏钙的体内成像

• 批准号: 7662923
• 负责人: Barry London
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662923
• 关键词: Acute; Animals; Anterior Descending Coronary Artery; Area; Arrhythmia; Autonomic nervous system; CMV promoter; Calcium; Canis familiaris; Cardiac; Cardiac Myocytes; Cell physiology; Cells; Cessation of life; Chest; Chronic; Data; Dependovirus; Development; Diagnostic; Disease; Engineering; Fiber Optics; Fluorescent Dyes; Functional disorder; Heart; Heart Diseases; Heart failure; Heterogeneity; Homeostasis; Image; Imaging technology; Implant; In Situ; In Vitro; Ions; Ischemia; Knowledge; Left; Life; Ligation; Light; Link; Location; London; Maps; Measurement; Measures; Methods; Modality; Modeling; Myocardial; Myocardial Infarction; Optics; Organ; Oryctolagus cuniculus; Pathology; Physiological; Play; Preparation; Proteins; Regulation; Reperfusion Therapy; Reporting; Role; RyR2; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; SERCA2a; Sarcoplasmic Reticulum; Serotyping; Signal Transduction; Site; Stress; Sudden Death; Surface; System; Techniques; Technology; Testing; United States; Variant; Ventricular; Ventricular Dysfunction; awake; base; heart cell; high risk; improved; in vivo; insight; nerve supply; novel; novel therapeutics; optical fiber; phospholamban; premature; pressure; public health relevance; reuptake; rhod-2; voltage

DESCRIPTION (provided by applicant): Calcium (Ca2+) oscillations underlie many important cellular processes that enable organ function, including contraction in the heart. Abnormalities in Ca2+ handling accompany most types of cardiac pathology, and may contribute to both ventricular dysfunction and arrhythmias. This proposal is aimed at developing a novel imaging technology to study spatial and temporal heterogeneities in Ca2+ transients in living animals. We will use adeno-associated virus serotype 9 (AAV-9) to stably deliver GCaMP2, a recently developed genetically encoded Ca2+-sensing molecule, into the hearts of living animals. Fiber optical probes (optrodes) will then be used to serially assess Ca2+ concentration at multiple transmural sites in both open- and closed-chest animals. We will test the hypothesis that transmural variation in Ca2+ transients during pathological states contributes to the development of cardiac dysfunction and arrhythmias. In Specific Aim 1, acute changes in Ca2+ transients will be studied in an open-chest rabbit model of ischemia-reperfusion during ligation of the left anterior descending coronary artery. In Specific Aim 2, chronic changes in Ca2+ transients will be studied in dogs with pacing-induced heart failure. These temporal and spatial measurements of in-situ Ca2+ transients at multiple sites in the heart will provide insights into the mechanisms by which abnormal Ca2+ handling contributes to cardiac dysfunction and arrhythmias in the setting of ischemia and heart failure. PUBLIC HEALTH RELEVANCE: Heart attacks and heart failure remain leading causes of illness and premature death in the United States. Calcium triggers the contraction during each heart beat, and calcium regulation is abnormal after a heart attack and in heart failure. In this proposal, we will develop a method to measure calcium concentrations in the heart cells of living animals and use this technology to better understand how abnormalities in calcium contribute to heart failure and sudden death.

描述（由申请人提供）：钙（Ca 2+）振荡是许多重要的细胞过程的基础，这些过程使器官功能得以实现，包括心脏收缩。Ca 2+处理的异常伴随大多数类型的心脏病理，并且可能导致心室功能障碍和心律失常。该提案旨在开发一种新的成像技术，以研究活体动物中Ca 2+瞬变的空间和时间异质性。我们将使用腺相关病毒血清型9（AAV-9），以稳定地提供GCaMP 2，最近开发的遗传编码的钙离子传感分子，到活动物的心脏。然后使用光纤探头（光极）连续评估开胸和闭胸动物多个透壁部位的Ca 2+浓度。我们将测试的假设，在病理状态下的跨壁变化的Ca 2+瞬变有助于心功能不全和心律失常的发展。在特定目标1中，将在开胸兔缺血-再灌注模型中研究左前降支冠状动脉结扎期间Ca 2+瞬变的急性变化。在特定目标2中，将在起搏诱导心力衰竭犬中研究Ca 2+瞬变的慢性变化。这些在心脏多个部位的原位Ca 2+瞬变的时间和空间测量将提供对异常Ca 2+处理在缺血和心力衰竭的情况下导致心脏功能障碍和心律失常的机制的见解。公共卫生相关性：心脏病发作和心力衰竭仍然是美国疾病和过早死亡的主要原因。钙在每次心跳时触发收缩，心脏病发作和心力衰竭后钙调节异常。在这项提案中，我们将开发一种方法来测量活体动物心脏细胞中的钙浓度，并利用这项技术更好地了解钙异常如何导致心力衰竭和猝死。