Biomechanics of early mammalian cardiogenesis

描述(申请人提供)：先天性心脏缺陷是最常见的出生缺陷之一，也是先天缺陷儿童死亡的主要原因。了解早期胚胎心脏的功能以及参与早期心脏发生的调控机制对心脏缺陷的研究具有重要意义。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素。因此，明确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新的治疗干预措施的开发至关重要。这种分析只能通过实时高分辨率胚胎成像进行。目前，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，我们不仅将确定心壁运动和液体运动之间的关键关系，以确定泵的特征，而且我们还将利用小鼠突变和胚胎干预来阐明无瓣膜哺乳动物心脏管推动血液的机制。传统上，人们一直认为早期的心管利用蠕动来输送血液。 通过心脏和早期的血管。然而，最近出现了另一种理论，即心管的功能类似于列堡泵，其工作方式是通过一个不对称的单一主动压迫部位和通过管子产生双向弹性波来工作。关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全面评估早期的心泵。此外，了解心脏泵的研究从未在哺乳动物胚胎中进行过，调节早期哺乳动物心脏管道功能的机制可能不能完全复制鸟类或硬骨鱼的机制。该项目的主要假设是，早期哺乳动物胚胎心管既不起蠕动泵的作用，也不像经典的单点受压的列保泵，尽管它利用了吸气机制和功能，通过多个部位的收缩波共振来发挥作用。我们建议使用我们开发的OCT小鼠胚胎活体成像方法，通过直接可视化和分析胚胎发育过程中的心跳和血流，来直接和明确地评估这一复杂的动态过程。这一建议将为早期哺乳动物心脏导管的泵浦机制提供新的、非常有价值的定量信息。它将为哺乳动物心脏发生、形态发生和畸胎学的活动态分析的广泛研究项目奠定基础，有助于更好地理解、预防和治疗人类心脏出生缺陷和胚胎衰竭。

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.