Biomechanics of early mammalian cardiogenesis

早期哺乳动物心脏发生的生物力学

• 批准号: 8547440
• 负责人: Irina Larina
• 金额: $ 38.67万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8547440
• 关键词: Active Sites; Biomechanics; Birds; Blood; Blood Viscosity; Blood flow; Cardiac; Cardiovascular system; Cause of Death; Child; Complex; Computer Analysis; Computer Simulation; Congenital Abnormality; Congenital Heart Defects; Data; Defect; Dependence; Development; Diagnosis; Diagnostic; Embryo; Embryonic Development; Embryonic Heart; Failure; Frequencies; Generations; Heart; Heart Atrium; Heart Rate; Home environment; Human; Image; Imagery; Imaging Techniques; Intervention; Lasers; Life; Liquid substance; Magnetic Resonance Imaging; Maps; Measurement; Measures; Methodology; Methods; Modeling; Molecular Genetics; Morphogenesis; Motion; Movement; Mus; Mutant Strains Mice; Myocardial Contraction; Nature; Optical Coherence Tomography; Pattern; Peristalsis; Prevention; Process; Protocols documentation; Publishing; Pump; Research; Research Personnel; Research Project Grants; Resolution; Site; Staging; Stimulus; Suction; Temperature; Teratology; Three-Dimensional Imaging; Tube; Vascular System; Viscosity; Work; base; cardiogenesis; embryo culture; fluorescence imaging; heart function; hemodynamics; innovation; insight; mouse model; novel; novel strategies; novel therapeutic intervention; prevent; public health relevance; teleost; theories

DESCRIPTION (provided by applicant): Congenital heart defects are among the most common birth defects and the leading cause of death in children born with congenital defects. Understanding how the early embryonic heart functions and what regulatory mechanisms are involved in early cardiogenesis is highly important for advancement of heart defects research. Biomechanical stimuli, including blood flow and heart contraction, are important regulators of cardiovascular development. Thus, defining how these mechanisms coordinate mammalian heart tube function and morphogenesis is critically important for the diagnosis of congenital heart defects and for the development of new therapeutic interventions to treat/prevent them. Such analysis can only be performed through live high- resolution embryonic imaging. At present, nearly nothing is known about the biomechanics of the early mammalian heart. In this proposal, we will not only identify key relationships between wall motion and fluid movement needed to characterize the pump, but we will also utilize mouse mutants and embryonic interventions to elucidate the mechanism by which valveless mammalian heart tube propels blood. Traditionally, it has been believed that the early heart tube uses peristalsis to move blood through the heart and early vessels. However, more recently, an alternative theory has emerged that the heart tube functions as a Liebau pump, which works by the means of an asymmetrically-located, single, active compression site and the generation of bidirectional elastic waves through the tube. There is still controversy among researchers as to which of these two mechanisms better describes the heart tube, and further studies are needed to fully evaluate the early heart pump. Also, studies to understand the heart pump have never been performed in mammalian embryos, and the mechanisms that regulate early mammalian heart tube function may not fully replicate those of avians or teleosts. The major hypothesis of this project is that early mammalian embryonic heart tube acts neither as a peristaltic pump nor as a classical Liebau pump with a single point of compression, though it utilizes suction mechanism and functions via resonance of contractile waves from multiple sites. We propose to directly and unambiguously assess this complex, dynamic process by direct visualization and analysis of the heartbeat and blood flow during embryonic development using the live OCT mouse embryo imaging approach which we developed. This proposal will provide novel highly valuable quantitative information about the pumping mechanism of the early mammalian heart tube. It will set a basis for a broad range of research projects on live dynamic analysis of mammalian cardiogenesis, morphogenesis and teratology, contributing to better understanding, prevention and treatment of cardiac birth defects and embryonic failures in humans.

描述（由申请人提供）：先天性心脏缺陷是最常见的出生缺陷之一，也是先天性缺陷儿童死亡的主要原因。了解早期胚胎心脏的功能以及心脏发生的调控机制对心脏缺陷研究的进展具有重要意义。生物力学刺激，包括血流和心脏收缩，是心血管发育的重要调节因子。因此，定义这些机制如何协调哺乳动物心管功能和形态发生对于先天性心脏缺陷的诊断和开发新的治疗干预措施来治疗/预防它们至关重要。这种分析只能通过活体高分辨率胚胎成像来进行。 目前，对早期哺乳动物心脏的生物力学几乎一无所知。在这项提案中，我们不仅将确定壁运动和流体运动之间的关键关系，需要表征泵，但我们也将利用小鼠突变和胚胎干预来阐明无瓣膜哺乳动物心管推进血液的机制。传统上，人们一直认为早期的心管利用蠕动来移动血液 穿过心脏和早期血管然而，最近出现了另一种理论，即心管起到Liebau泵的作用，其通过不对称定位的单个主动压缩部位和通过管产生双向弹性波来工作。对于这两种机制中哪一种更好地描述了心管，研究人员之间仍然存在争议，需要进一步的研究来充分评估早期心脏泵。此外，从未在哺乳动物胚胎中进行过了解心脏泵的研究，并且调节早期哺乳动物心管功能的机制可能无法完全复制鸟类或硬骨鱼类的机制。 该项目的主要假设是，早期哺乳动物胚胎心管既不作为蠕动泵，也不作为具有单点压缩的经典Liebau泵，但它利用抽吸机制，并通过来自多个部位的收缩波的共振来发挥作用。我们建议使用我们开发的活OCT小鼠胚胎成像方法，通过直接可视化和分析胚胎发育过程中的心跳和血流，直接和明确地评估这个复杂的动态过程。 这一建议将提供新的非常有价值的定量信息的早期哺乳动物心管的泵送机制。它将为哺乳动物心脏发生、形态发生和畸形学的活体动态分析的广泛研究项目奠定基础，有助于更好地了解、预防和治疗人类心脏出生缺陷和胚胎衰竭。