Role of mechanical forces in cardiac s-looping

描述(申请人提供)：尽管心脏发育的遗传和分子机制受到了相当大的关注，但驱动这些复杂形状变化的生物力学力量在很大程度上被忽视了。这个项目的目标是加深我们对胚胎心脏发育的理解。利用实验和计算相结合的方法，该项目将揭示将简单的直管转变为四腔泵的显著形状变化的原因。该项目将专注于一个被称为“S环”的发展阶段，即最初位于原始脑室下方的原始心房移动到其位于脑室上方的最终位置。本课题有两个具体目标：(1)通过实验对S环路进行了详细的定性和定量表征。然后开发一个计算机模型，其中包括实验确定的内部载荷、肌动蛋白纤维方向和边界条件。(2)利用目标1中建立的计算机模型确定驱动早期心脏S环的机械力的分布。雏鸡心脏的发育与人类非常相似，将被用作实验模型。有限元技术将被用于开发计算机模型。对于第一个目标，S环的特征将首先使用荧光标记测量局部形态发生应力场和应变场，并通过共聚焦显微镜确定局部肌动蛋白的取向。此外，化学扰动将被用来确定肌动蛋白聚合和细胞骨架收缩的可能作用-这两个致动器在c-环中是重要的，这是S-环之前的。此外，还将使用机械扰动来研究S心脏各组成部分所施加的力。对于第二个目标，将建立S回环的计算模型。然后，通过比较实验和模型预测的局部结果(即应力场和应变场，机械扰动的结果)和全局结果(即总体形状、长度和直径的变化)，将确定导致S成环的力分布。与公共健康的相关性根据美国心脏协会的数据，100万美国人患有某种形式的先天性心脏病，每年有3.5万名婴儿出生时患有某种形式的先天性心脏病。异常循环是先天性心脏病的主要原因之一。这个项目将阐明人们对循环机制知之甚少的问题。 公共卫生相关性：项目描述根据美国心脏协会的数据，100万美国人患有某种形式的先天性心脏病，每年有3.5万名婴儿出生时患有某种形式的先天性心脏病。异常循环是先天性心脏病的主要原因之一。这个项目将阐明人们对循环机制知之甚少的问题。1

DESCRIPTION (provided by applicant): Although the genetic and molecular mechanisms of heart development have received considerable attention, the biomechanical forces driving these complex shape changes have largely been ignored. The goal of this project is to make inroads into our understanding of embryonic heart development. Using a combined experimental and computational approach, the project will uncover the forces responsible for the remarkable shape changes that transform a simple straight tube into a four-chambered pump. The project will focus on a period of development termed "s-looping", when the primitive atrium, which initially lies inferior to the primitive ventricle, moves to its definitive position superior to the ventricle. The project has two specific aims: (1) Carefully characterize s-looping qualitatively and quantitatively via experiments. Then develop a computer model that includes internal loads, actin fiber orientations, and boundary conditions as determined by experiments. (2) Use the computer model developed in Aim 1 to determine the distribution of mechanical forces that drive early cardiac s-looping. The chick heart, whose development closely parallels that in humans, will be used as the experimental model. The finite element technique will be used to develop computer models. For the first aim, s-looping will first be characterized by measuring local morphogenetic stress and strain fields using fluorescent labeling and determining the local actin orientations by confocal microscopy. In addition, chemical perturbations will be used to determine possible roles for actin polymerization and cytoskeletal contraction - two actuators that are important in c-looping, which precedes s-looping. Also, mechanical perturbations will be used to investigate forces applied by the various constituent parts of the s-looping heart. For the second aim a computational model for s-looping will be constructed. Then, by comparing the experimental and model-predicted local (i.e., stress and strain fields, outcomes of mechanical perturbations) and global (i.e., gross shape, length, and diameter changes) outcomes, the force distributions responsible for s-looping will be determined. Relevance to Public Health According to data from the American Heart Association, 1,000,000 Americans have some form of congenital heart defect and 35,000 babies are born every year with some form of congenital heart disease. Abnormal looping is a primary reason for congenital heart disease. This project will shed light on the poorly-understood mechanics of looping. PUBLIC HEALTH RELEVANCE: Project Narrative According to data from the American Heart Association, 1,000,000 Americans have some form of congenital heart defect and 35,000 babies are born every year with some form of congenital heart disease. Abnormal looping is a primary reason for congenital heart disease. This project will shed light on the poorly-understood mechanics of looping. 1