Optical pacing of the embryonic heart

胚胎心脏的光学起搏

• 批准号: 8356216
• 负责人: MICHAEL W. JENKINS
• 金额: $ 23.55万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-17 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356216
• 关键词: Affect; Arrhythmia; Biological Assay; Biomechanics; Birds; Blood flow; Cardiac; Complex; Congenital Abnormality; Congenital Heart Defects; Data; Defect; Development; Electrophysiology (science); Embryo; Embryonic Heart; Etiology; Exploratory/Developmental Grant; Feedback; Gene Expression; Genes; Goals; Heart; Heart Rate; Image; Investigation; Lead; Length; Ligation; Light; Lighting; Live Birth; Location; Measures; Mechanics; Methods; Modeling; Molecular; Monitor; Morphogenesis; Morphology; Mus; Newborn Infant; Operative Surgical Procedures; Optical Coherence Tomography; Optics; Outcome; Pacemakers; Pathway interactions; Physiologic pulse; Play; Procedures; Protocols documentation; Quail; Resolution; Risk; Role; Shapes; Signal Transduction; Staging; Structure; Study Section; Suggestion; Techniques; Technology; Temperature; Time; Tissue Engineering; Tissues; Tube; Zebrafish; cardiogenesis; effective therapy; hemodynamics; in vivo; new technology; novel; research study; response; shear stress; tool

DESCRIPTION (provided by applicant): Our long-term objective is to determine the influence biophysical forces have on heart development and how alterations of these forces early in development can lead to congenital heart defects (CHDs). CHDs are extremely prevalent affecting almost 36,000 newborns in the US each year, or 9 out of 1,000 live births. In order to tease apart what molecular pathways are being regulated by biomechanics, we will be developing new technology (optical pacing) capable of perturbing cardiac dynamics in precise ways. Previous perturbation techniques have involved gross manipulations (vessel ligation, conotruncal banding, etc.) that do not offer the necessary control to determine the exact influences of biomechanics on development. We have demonstrated that optical pacing is capable of consistently pacing early embryonic quail hearts in vivo in a precise manner over a range of developmental stages without causing damage to the tissue. Recent data shows that we can modify the level of regurgitant flow in the outflow tract thereby altering oscillatory shear stress (OSS). It has been suggested that shear forces in the outflow tract are needed for normal development of valves and septa. Outflow tract defects which make up 15-20% of CHDs are very serious requiring surgical intervention. As a demonstration of the potential of OP, we will create a model of abnormal regurgitant flow in the outflow tract and investigate the impact of this change in shear force on molecular expression and morphogenesis during cardiac development. Experiments will be conducted to determine the optimal energy requirements for optical pacing and these optimal settings will be utilized to develop optical pacing protocols that consistently change the levels OSS in the outflow tract to precise degrees. Optical coherence tomography will be employed to refine optical pacing methods and to measure hemodynamics and morphology both during and after optical pacing. Upon completion, we will have optimized and characterized OP as a new experimental tool, used that tool to create a model of abnormal regurgitant flow in the outflow tract, and investigated the impact of this change in shear force on gene expression and morphogenesis during cardiac development. This experimental tool will be valuable more broadly for uncovering the mechanisms of mechanically transduced signaling in the early developing heart, which will enable us to develop a better understanding of the etiology of congenital defects. OP has the potential to manipulate cardiac function in multiple ways and may be capable of producing other models of cardiac irregularities (e.g. arrhythmias, abnormal levels of regurgitant flow in the atrioventricular junction, etc.). PUBLIC HEALTH RELEVANCE: The mechanisms behind congenital heart defects (CHDs) are largely unclear, and biomechanical forces likely play a role during the development of CHDs. This project aims to develop new technology (optical pacing) capable of perturbing biomechanical forces in the heart in order to elucidate the complex interplay between structure and function in the developing heart in vivo. Better understanding of the origins and progression of congenital heart defects can potentially lead to better prediction of outcomes, and earlier, more effective treatments.

描述(申请人提供)：我们的长期目标是确定生物物理力量对心脏发育的影响，以及这些力量在发育早期的变化如何导致先天性心脏缺陷(CHDS)。CHDS非常普遍，每年在美国影响近3.6万名新生儿，或者说每1000名活产儿中就有9名。为了梳理出哪些分子途径受到生物力学的调控，我们将开发能够以精确方式扰乱心脏动力学的新技术(光学起搏)。以前的摄动技术涉及到粗大的操作(血管结扎、圆锥干束扎术等)。这不能提供必要的控制来确定生物力学对发育的确切影响。我们已经证明，光学起搏能够在体内以精确的方式在一系列发育阶段保持对早期胚胎鹌鹑心脏的起搏，而不会对组织造成损害。最近的数据表明，我们可以改变流出道中的返流水平，从而改变振荡切变。 应激(OSS)。有人认为，流出道中的剪切力是阀门和隔膜正常发展所必需的。流出道缺陷占先天性心脏病的15-20%，是非常严重的疾病，需要手术治疗。为了展示OP的潜力，我们将创建流出道中异常返流的模型，并研究其影响 心脏发育过程中剪切力对分子表达和形态发生的影响。将进行实验以确定光学起搏的最佳能量需求，并将利用这些最佳设置来开发光学起搏协议，该协议 始终如一地改变流出道中OSS的水平，以精确的程度。光学相干断层扫描将被用来改进光学起搏方法，并测量光学起搏中和之后的血流动力学和形态。完成后，我们将优化和表征OP作为一种新的实验工具，使用该工具创建流出道中异常返流流动的模型，并调查这种剪切力变化对 心脏发育过程中的基因表达和形态发生。这一实验工具对于揭示心脏发育早期机械转导信号的机制将具有更广泛的价值，使我们能够更好地理解先天性缺陷的病因。OP有可能以多种方式操控心脏功能，并可能产生其他心脏异常模式(如心律失常、房室交界处反流水平异常等)。 公共卫生相关性：先天性心脏缺陷(CHDS)背后的机制在很大程度上尚不清楚，生物力学力量可能在CHDS的发展过程中发挥作用。该项目旨在开发能够扰乱心脏生物机械力的新技术(光学起搏)，以阐明体内发育中的心脏结构和功能之间的复杂相互作用。更好地了解先天性心脏病的起源和发展可能会导致更好的预后预测，以及更早、更有效的治疗。