Biomechanics of early mammalian cardiogenesis

早期哺乳动物心脏发生的生物力学

• 批准号: 8969458
• 负责人: Irina Larina
• 金额: $ 3.38万
• 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/8969458
• 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; Health; 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; model building; mouse model; novel; novel strategies; novel therapeutic intervention; prevent; 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先天缺陷和先天性缺陷儿童的主要死亡原因。了解早期的胚胎心脏功能以及早期心脏病发生的哪些调节机制对于进步心脏缺陷研究非常重要。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剂。因此，定义这些机制如何协调哺乳动物的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以治疗/预防它们至关重要。这种分析只能通过实时高分辨率胚胎成像进行。 目前，关于早期哺乳动物心脏的生物力学几乎一无所知。在此提案中，我们不仅将确定表征泵所需的壁运动与流体运动之间的关键关系，而且我们还将利用小鼠突变体和胚胎干预措施来阐明valveless哺乳动物心管促进血液的机制。传统上，人们相信早期的心管使用蠕动移动血液 通过心脏和早期的船只。然而，最近，一种替代理论已经出现了心管充当Liebau泵，该泵的起作用是通过不对称的，单个的，主动的压缩位点和通过管道的双向弹性波产生的方法。研究人员之间仍然存在争议，即这两种机制中的哪种更好地描述了心脏管，需要进一步的研究来充分评估早期心脏泵。同样，了解心脏泵的研究从未在哺乳动物的胚胎中进行，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禽类或硬骨鱼的功能。 该项目的主要假设是，早期的哺乳动物胚胎心管既不是蠕动泵，也不是具有单个压缩点的经典liebau泵，尽管它通过来自多个地点的收缩波的共振来利用吸力机制和功能。我们建议使用我们开发的实时OCT小鼠胚胎成像方法直接可视化和分析胚胎发育过程中心跳和血流的直接可视化和分析，直接和明确地评估了这一复杂的动态过程。 该提案将提供有关早期哺乳动物心管的抽水机理的新型高价定量信息。它将为对哺乳动物心脏病，形态发生和畸形的实时动态分析的广泛研究项目树立基础，从而有助于更好地理解，预防和治疗人类心脏出生缺陷和胚胎失败。