Optical Tools to Assess the Role of Hemodynamics in the Development of Congenital Heart Defects

评估血流动力学在先天性心脏缺陷发展中的作用的光学工具

• 批准号: 8985102
• 负责人: MICHAEL W. JENKINS
• 金额: $ 61.27万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8985102
• 关键词: 3-Dimensional; Ablation; Affect; Alcohols; Algorithmic Software; Algorithms; American; Biological Assay; Blood flow; Cardiac; Cardiac Output; Cardiac development; Cardiovascular system; Chemical Exposure; Complex; Congenital Abnormality; Congenital Heart Defects; Defect; Development; Double Outlet Right Ventricle; Early Diagnosis; Embryo; Embryonic Development; Embryonic Heart; Etiology; Experimental Models; Feedback; Genetic; Heart; Heart Rate; Hypoxia; Image; Knowledge; Lasers; Lead; Light; Link; Location; Measurement; Measures; Methods; Modification; Molecular; Monitor; Morphology; Nerve; Neural Crest Cell; Neurons; Normalcy; Optical Coherence Tomography; Optics; Pathway interactions; Pattern; Penetration; Phenotype; Physiologic pulse; Play; Protocols documentation; Research Personnel; Role; Side; Speed; Spottings; Staging; Stroke Volume; Structural defect; Structure; System; Techniques; Technology; Testing; Time; United States; blood flow measurement; cardiogenesis; clinically relevant; computerized data processing; design; design and construction; developmental cardiology; genetic manipulation; hemodynamics; in vivo; public health relevance; reconstruction; shear stress; tool

 DESCRIPTION (provided by applicant): Congenital heart defects (CHDs) are one of the most common and devastating birth defects, afflicting 32,000 babies born in the United States each year, and over 1 million Americans alive today. Altered hemodynamics during development has been shown to be a contributing factor to CHDs, regardless of whether the initial trigger is environmental or genetic. However, there is currently a lack of appropriate tools for studying the effects of clinically relevant hemodynamic perturbations on the development of later defects. The objective of this project is to design, construct, and apply the tools necessary to measure and precisely perturb hemodynamics in early embryonic development and then detect and quantify the resultant CHDs that develop. We propose to use optical techniques for both measurement and perturbation. We have previously demonstrated that optical coherence tomography (OCT) can measure many hemodynamic parameters, including heart rate, cardiac output, stroke volume, shear stress, and regurgitation. For this project, we will construct an ultrahigh-speed OCT system using new hardware and software algorithms to acquire hemodynamic parameters in real-time. We will build the system to be able to conduct longitudinal imaging studies of multiple embryos in parallel. New optical control (OC) technology has been developed for stimulating and inhibiting nerves and neurons, using pulsed infrared light to induce thermal effects. We have recently adapted this technology to stimulate embryonic hearts both in vivo and ex vivo and have a proof-of-concept demonstration for inhibiting cardiac activity. OC enables precise control of heart rate and development of advanced OC protocols will enable complex alteration of the heart's beat patterns (e.g. altered atrioventricular delay). We will perform further optimization of OC parameters and integrate OC into our ultrahigh-speed OCT system. This will enable the development of a closed-loop control system utilizing real-time OCT parameters as feedback to maintain hemodynamic parameters at desired values for long periods of time, even as the embryo grows and develops. We will also construct a double-sided Bessel-beam OCT system to obtain, in conjunction with optical clearing techniques, sufficient depth penetration to acquire structural images of later stage 4-chambered embryonic hearts. Finally, after validating these systems, we will apply this technology to test the hypothesis that altered regurgitation and shear stress on the developing cardiac cushions (valve precursors) will lead to valve defects. We will also explore whether compromised cardiac cushions also lead to misalignment of the great vessels (e.g. double outlet right ventricle). Upon completion, we will have developed tools and gathered significantly more information on when, how, and to what degree the developing cardiovascular system is most vulnerable to abnormal hemodynamics. With this knowledge, we will be better equipped to determine which molecular pathways are most influenced by altered hemodynamics, to develop earlier detection strategies, and potentially to treat CHDs more effectively.

 描述（由适用提供）：先天性心脏缺陷（CHD）是最常见和毁灭性的先天缺陷之一，每年在美国出生的32,000名婴儿，今天有超过100万美国人。发育过程中的血液动力学改变已被证明是CHD的一个促成因素，而不管最初的触发是环境还是遗传。但是，目前缺乏适当的工具来研究临床相关的血液动力学扰动对后来缺陷的发展的影响。该项目的目的是设计，构建和应用在早期胚胎发育中测量和精确扰动血液动力学所需的工具，然后检测和量化所得的CHD。我们以前已经证明，光学相干断层扫描（OCT）可以测量许多血液动力学参数，包括心率，心输出量，中风体积，剪切应力和反流。对于此项目，我们将使用新的硬件和软件算法构建一个超高速度OCT系统，以实时获取血液动力学参数。我们将构建该系统，以便能够并行进行多个胚胎的纵向成像研究。已经开发了用于刺激和抑制神经和神经元的新的光学控制（OC）技术，使用脉冲红外光诱导热效应。最近，我们对这项技术进行了调整，以刺激体内和Ex Vivo的胚胎心脏，并进行了概念验证示范，以抑制心脏活性。 OC可以精确控制心率和高级OC方案的发展，将使心脏节拍模式的复杂改变（例如，心室延迟改变）。我们将进一步优化OC参数并集成的OC进入我们的超高速度OCT系统。这将使使用实时OCT参数作为反馈的闭环控制系统的开发，即使胚胎成长和发展，也可以长时间以所需值维持血液动力学参数。我们还将构建一个双面的贝塞尔束OCT系统，以与光学清除技术结合使用足够的深度穿透，以获取后期4腔的胚胎胚胎心脏的结构图像。最后，在验证了这些系统之后，我们将应用这项技术来测试以下假设，即对发育中的心脏垫（阀前体）改变了反流和剪切应力将导致瓣膜缺陷。我们还将探索折衷的心脏垫子是否也导致了大血管的未对准（例如双出出口右心室）。完成后，我们将开发工具，并收集更多有关何时，如何以及在何种程度和在何种程度上的心血管系统最容易受到异常血液动力学的信息。有了这些知识，我们将有更好的能力来确定哪些分子途径受到血液动力学改变，制定早期检测策略的影响，并有可能更有效地治疗CHD。