Electrical Biophysical Forces Impact Cardiac Morphogenesis

电生物物理力影响心脏形态发生

• 批准号: 8678969
• 负责人: Neil C Chi
• 金额: $ 31.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-10 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8678969
• 关键词: Affect; Animals; Architecture; Biomechanics; Biomedical Engineering; Biophysical Process; Calcium; Cardiac; Cardiac Myocytes; Cell Adhesion Molecules; Cell Shape; Cell Therapy; Cell physiology; Cell-Cell Adhesion; Cells; Complex; Congenital Abnormality; Coupled; Coupling; Cytoskeletal Proteins; Development; Diagnosis; Embryo; Environmental Risk Factor; Future; Genes; Heart; Homeostasis; Human; Imaging Device; In Vitro; Individual; Live Birth; Mechanics; Mediating; Molecular; Morphogenesis; Morphology; Mutation; Myocardium; Patients; Pattern; Physiological; Play; Prevention; Process; Proteins; Regulation; Regulator Genes; Rewards; Role; Sarcomeres; Shapes; System; Testing; Tissues; Troponin T; Zebrafish; cardiogenesis; cell motility; congenital heart disorder; electric field; heart electrical activity; hemodynamics; in vivo; injured; insight; interdisciplinary approach; migration; mutant; novel; prenatal; programs; spatiotemporal

DESCRIPTION (provided by applicant): Congenital Heart Disease (CHD) is the most common birth defect in humans affecting nearly one out of every one-hundred live births and is responsible for the vast majority of prenatal losses. Although several cardiac gene regulatory programs are known to play an important role in cardiac development, our understanding of how biophysical forces act alone, together, or in concert with these cardiac transcriptional programs to modulate heart morphogenesis is far from complete. Thus, studies which illuminate the underlying cellular, molecular, and physiologic mechanisms of how biophysical forces impact cardiac morphogenesis may ultimately aid in diagnosis and treatment of patients predisposed for CHD. Past studies have shown that biomechanical forces such as cardiomyocyte contractility and intracardiac hemodynamic flow may regulate this process in vivo. Though in vitro studies suggest that cardiomyocytes can realign themselves according to electrical conduction directionality, it remains unclear as to whether these natural cardiac conduction currents can generate electric fields sufficient to direct cardiomyocyte cell shape and migration and subsequent cardiac morphogenesis in vivo. Recent animal studies have suggested that electrical conduction may influence overall architecture of the developing vertebrate heart; however, assessing the individual contributions of electrical cardiac conduction, mechanical cardiac contraction and hemodynamic forces to overall heart morphogenesis is difficult because these biophysical forces are intimately coupled in the intact heart through excitation- contraction coupling. As a result, to uncouple these biophysical factors in vivo, we have recently exploited the silent heart zebrafish cardiac mutant, which displays nonbeating, but electrically conducting hearts due to a mutation in the sarcomeric gene, cardiac troponin T, and discovered that electrical conduction exclusive of contractile and hemodynamic forces can directly participate in in vivo remodeling and morphogenesis of the vertebrate heart. Thus, we hypothesize that cardiac electrical forces play a critical role toward maintaining cardiomyocyte morphology and overall cardiac morphogenesis during vertebrate heart development through regulation of cardiomyocyte calcium transient patterns/gradients. Our specific aims are: 1) to investigate the impact of electrical forces on cardiac morphogenesis in vivo; 2) to investigate whether cardiac electrical forces may regulate cellular proteins involved in cardiomyocyte morphology; and 3) to investigate the influences of cardiac electrical forces on the spatiotemporal organization of cardiomyocyte calcium transients/flickers. Overall, our interdisciplinary approach including the utilization of a genetically tractable yet optically transparent animal system as well as novel bioengineering and imaging tools will provide in vivo mechanistic insight into how electrical forces may directly impact cardiac morphogenesis. These studies may not only prove rewarding towards our understanding of CHD, but also provide additional insight towards optimizing integration and alignment of engrafted embryonic cardiomyocytes in injured myocardium for future cardiac cell-based therapy.

描述(申请人提供)：先天性心脏病(CHD)是人类最常见的出生缺陷，几乎每一百个活产中就有一个受到影响，并且是绝大多数产前损失的原因。尽管已知一些心脏基因调控程序在心脏发育中发挥重要作用，但我们对生物物理力量如何单独、共同或与这些心脏转录程序一起调节心脏形态发生的了解还远远不完整。因此，阐明生物物理力如何影响心脏形态发生的潜在细胞、分子和生理机制的研究最终可能有助于冠心病易感性患者的诊断和治疗。过去的研究表明，生物力学力量，如心肌细胞收缩和心内血流可能在体内调节这一过程。虽然体外研究表明心肌细胞可以根据电传导方向性进行自我调整，但目前尚不清楚这些自然的心脏传导电流是否能够产生足够的电场来指导心肌细胞的形态和迁移以及随后的在体心脏形态发生。最近的动物研究表明，电传导可能影响发育中的脊椎动物心脏的整体结构；然而，很难评估心脏电传导、机械心脏收缩和血流动力对整体心脏形态发生的单独贡献，因为这些生物物理力通过兴奋-收缩耦合在完整的心脏中紧密耦合。因此，为了在体内解偶联这些生物物理因子，我们最近利用了沉默的心脏斑马鱼心脏突变体，它由于肌节基因心肌肌钙蛋白T的突变而表现为不跳动，但具有导电功能，并发现除了收缩和血流动力外，电传导可以直接参与脊椎动物心脏的活体重建和形态发生。因此，我们假设，在脊椎动物心脏发育过程中，心脏电场力通过调节心肌细胞钙瞬变模式/梯度，在维持心肌细胞形态和整体心脏形态发生方面起着关键作用。我们的具体目标是：1)研究电场力对在体心脏形态发生的影响；2)研究心脏电场力是否可能调节与心肌细胞形态有关的细胞蛋白；3)研究心脏电场力对心肌细胞钙瞬变/闪烁的时空组织的影响。总体而言，我们的跨学科方法，包括利用遗传上易处理但光学透明的动物系统，以及新的生物工程和成像工具，将在体内提供对电动力如何直接影响心脏形态发生的机械洞察。这些研究可能不仅有助于我们对CHD的理解，而且也为将来基于心肌细胞的治疗优化移植胚胎心肌细胞在受损心肌中的整合和排列提供了新的见解。