Role of mechanical forces in cardiac s-looping

机械力在心脏 s 环循环中的作用

• 批准号: 8177199
• 负责人: ASHOK RAMASUBRAMANIAN
• 金额: $ 30万
• 依托单位: UNION COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8177199
• 关键词: Actins; American; American Heart Association; Attention; Automobile Driving; Biological; Biology; Biomechanics; Biomedical Engineering; Caliber; Cardiac; Cell Shape; Cell division; Chick Embryo; Collaborations; Collecting Tube; Complement; Complex; Computer Simulation; Computing Methodologies; Confocal Microscopy; Congenital Heart Defects; Cytoskeleton; Data; Development; Dimensions; Elements; Embryonic Heart; Engineering; Ensure; Event; Experimental Models; Extracellular Matrix; Fiber; Foundations; Goals; Heart; Heart Atrium; Hour; Human; Inferior; Label; Lead; Length; Light; Measures; Mechanics; Modeling; Molecular Genetics; Morphogenesis; Organ; Outcome; Pathway interactions; Phase; Positioning Attribute; Public Health; Pump; Role; Shapes; Splanchnopleure; Stress; Students; Study models; Supervision; Techniques; Tube; Tubular formation; Veins; Work; cardiogenesis; chemical addition; college; congenital heart disorder; design; driving force; polymerization; post-doctoral training; research study

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

描述（由申请人提供）：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。这个项目的目标是使我们对胚胎心脏发育的理解取得进展。该项目采用实验和计算相结合的方法，将揭示将简单的直管转变为四腔泵的显着形状变化的力量。该项目将集中在一个时期的发展称为“s-循环”，当原始心房，最初位于原始心室下方，移动到其最终位置上级心室。 该项目有两个具体目标：（1）通过实验定性和定量地仔细描述s-循环。然后开发一个计算机模型，包括内部负载，肌动蛋白纤维的方向，和边界条件，由实验确定。(2)使用目标1中开发的计算机模型来确定驱动早期心脏S环的机械力的分布。鸡的心脏，其发展密切相似，在人类中，将被用作实验模型。有限元技术将用于开发计算机模型。 对于第一个目标，S-循环将首先通过使用荧光标记测量局部形态发生应力和应变场，并通过共聚焦显微镜确定局部肌动蛋白方向来表征。此外，化学扰动将用于确定肌动蛋白聚合和细胞骨架收缩的可能作用-这两个驱动器是重要的c-循环，这之前的s-循环。此外，机械扰动将被用来研究由s-循环心脏的各个组成部分施加的力。对于第二个目标的计算模型的s-循环将被构造。然后，通过比较实验和模型预测的局部（即，应力和应变场，机械扰动的结果）和全局（即，总的形状、长度和直径变化）结果，将确定造成S形成环的力分布。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35,000名婴儿出生时患有某种形式的先天性心脏病。先天性心脏病的主要病因是先天性心脏病。这个项目将阐明对循环机制的理解不足。 公共卫生关系：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35,000名婴儿出生时患有某种形式的先天性心脏病。先天性心脏病的主要病因是先天性心脏病。这个项目将阐明对循环机制的理解不足。1

项目成果

On the role of intrinsic and extrinsic forces in early cardiac S-looping.

• DOI: 10.1002/dvdy.23968
• 发表时间: 2013-07
• 期刊: DEVELOPMENTAL DYNAMICS
• 影响因子: 2.5
• 作者: Ramasubramanian, Ashok;Chu-Lagraff, Quynh B.;Buma, Takashi;Chico, Kevin T.;Carnes, Meagan E.;Burnett, Kyra R.;Bradner, Sarah A.;Gordon, Shaun S.
• 通讯作者: Gordon, Shaun S.

On the Biomechanics of Cardiac S-Looping in the Chick: Insights From Modeling and Perturbation Studies.

关于小鸡心脏 S 环的生物力学：来自建模和扰动研究的见解。

• DOI: 10.1115/1.4043077
• 发表时间: 2019
• 期刊: Journal of biomechanical engineering
• 作者: Ramasubramanian,Ashok;Capaldi,Xavier;Bradner,SarahA;Gangi,Lianna
• 通讯作者: Gangi,Lianna