Biomechanics of early mammalian cardiogenesis

早期哺乳动物心脏发生的生物力学

• 批准号: 10428362
• 负责人: Irina Larina
• 金额: $ 54.35万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428362
• 关键词: Address; Animals; Biological; Biomechanics; Blood Viscosity; Blood flow; Candidate Disease Gene; Cardiac; Cardiac development; Cardiovascular system; Cell Differentiation process; Cells; Cessation of life; Collagen; Complement; Congenital Abnormality; Congenital Heart Defects; Contracts; Data; Defect; Deposition; Detection; Development; Diagnostic; Embryo; Ensure; Etiology; Extracellular Matrix; Extracellular Matrix Proteins; FURIN gene; Failure; Gene Expression; Gene Targeting; Genetic; Genetic Transcription; Goals; Grant; Heart; Heart failure; Homeostasis; Human; Image; Individual; Infant; Laboratories; Link; Live Birth; Measurement; Mechanics; Methodology; Methods; Modeling; Molecular; Molecular Genetics; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Myocardial Contraction; Nature; Optical Coherence Tomography; Optics; Pathway interactions; Pharmacology; Phenotype; Physiologic pulse; Population; Positioning Attribute; Prevention; Pump; Regulation; Resolution; Role; Signal Pathway; Stimulus; Structure; System; Techniques; Testing; Three-Dimensional Imaging; Time; Transglutaminases; Tube; Viscosity; base; cardiogenesis; collagenase; crosslink; elastography; embryo culture; experimental study; genetic makeup; hemodynamics; image guided; in vivo; innovation; insight; mechanical properties; mechanical stimulus; mouse model; mutant; novel; novel therapeutic intervention; optogenetics; prevent; response; sex; shear stress; transcriptome sequencing

PROJECT SUMMARY Human congenital heart defects (CHD) are very common, occurring in nearly 1% of live births. Moreover, cardiovascular (CV) failures are the leading cause of birth defect- related deaths in infants. It is well established that biomechanical stimuli are important regulators of CV development. Thus, defining how mechanical factors are integrated with genetic pathways to coordinate mammalian heart tube function and morphogenesis is critically important for understanding CHD and heart failure. Such information will also factor heavily into strategies for new therapeutic interventions to treat/prevent CHD. Toward that end, the mouse model is an excellent system in which to study human congenital defects. However, due to the internal nature of mammalian development, analysis of heart biomechanics is challenging. Through the previous cycle of this grant, we established a set of innovative optical coherence tomography (OCT) approaches for live, high-resolution 3D imaging and quantitative assessment of mouse embryo CV dynamics. These techniques were applied to analysis of the pumping mechanism of the E8.5 to E10.5 mouse heart and characterization of mutant phenotypes mimicking human CHDs. Therefore, we are in a unique position to investigate how mechanical stimuli of cardiodynamics and blood flow are linked to molecular/genetic changes during early cardiac differentiation in living mouse embryos. While multiple studies suggest that cardiac contraction, blood flow and stiffness each influence CV development, due to the interdependence of these factors, their individual roles are unknown. The goal of this proposal is to define the differential role of cardiac contraction and flow-induced shear stress in regulating mechanical homeostasis (stiffness) and cell fate decisions in vivo. These experiments will specifically address the context-dependent interplay between these factors, which likely vary between cardiac regions with different functional roles, such as in actively contracting regions versus the passively contracting outflow tract (OFT). Scientific Premise, Scientific Rigor, and Relevant Biological Variables: This proposal will fill a significant gap in the field of early mammalian cardiac development and define the role of cardiac forces in maintaining mechanical homeostasis and cell differentiation. This information will lead to a better understanding, prevention and treatment of CHD and embryonic cardiac failures in humans. The proposed study is supported by strong preliminary data. We carefully articulated the number of experimental animals to be used, the precise genetic makeup of these animals, and the rationale for the choice of the models. Sex as a biological variable is considered and addressed in the proposal. Extensive details are provided to ensure that preliminary and proposed experiments can be replicated in other laboratories.

项目摘要 人类先天性心脏缺陷（CHD）非常普遍，近1％发生 活产。此外，心血管（CV）失败是出生缺陷的主要原因 - 婴儿相关死亡。众所周知，生物力学刺激很重要 简历开发的监管机构。因此，定义如何整合机械因素 具有协调哺乳动物心管功能和形态发生的遗传途径 至关重要的是了解冠心病和心力衰竭。这些信息也将 大量将新的治疗干预措施治疗/预防冠心病的策略取得因素。 为此，鼠标模型是研究人类的出色系统 先天性缺陷。但是，由于哺乳动物发育的内部性质， 心脏生物力学的分析具有挑战性。 通过这笔赠款的上一个周期，我们建立了一组创新的光学 相干断层扫描（OCT）用于现场高分辨率3D成像和 小鼠胚胎CV动力学的定量评估。这些技术是 应用于E8.5至E10.5小鼠心脏的泵送机理的分析 模仿人类疾病的突变表型的表征。因此，我们在 独特的位置来研究心脏动力学和血流的机械刺激 与生命早期心脏分化期间的分子/遗传变化有关 小鼠胚胎。 而多项研究表明心脏收缩，血流和僵硬 由于这些因素的相互依存而影响简历的发展，他们的个体 角色是未知的。该提议的目的是定义心脏的差异作用 收缩和流动诱导的剪切应力在调节机械稳态时 （刚度）和细胞命运在体内决策。这些实验将专门解决 这些因素之间的上下文依赖性相互作用，这种因素可能在心脏之间有所不同 具有不同功能角色的区域，例如在积极收缩区域与 被动收缩流出道（法）。 科学前提，科学严谨和相关的生物学变量：这 提案将填补早期哺乳动物心脏发展领域的显着空白 并定义心脏在维持机械稳态和细胞中的作用 分化。这些信息将导致更好的理解，预防和 治疗人类中冠心病和胚胎心脏衰竭。拟议的研究是 由强大的初步数据支持。我们仔细阐明了 要使用的实验动物，这些动物的精确遗传构成， 选择模型的理由。性别作为生物变量被考虑，并且 在提案中解决。提供了广泛的详细信息，以确保初步和 建议的实验可以在其他实验室中复制。

项目成果

Evaluating the effects of maternal alcohol consumption on murine fetal brain vasculature using optical coherence tomography.

• DOI: 10.1002/jbio.201700238
• 发表时间: 2018-05
• 期刊: Journal of biophotonics
• 影响因子: 2.8
• 作者: Raghunathan R;Wu C;Singh M;Liu CH;Miranda RC;Larin KV
• 通讯作者: Larin KV

A dual-modality optical coherence tomography and selective plane illumination microscopy system for mouse embryonic imaging.

用于小鼠胚胎成像的双模态光学相干断层扫描和选择性平面照明显微镜系统。

• DOI: 10.1109/embc.2017.8037742
• 发表时间: 2017
• 期刊: Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference
• 作者: ChenWu;ShihaoRan;Le,Henry;Singh,Manmohan;Larina,IrinaV;Mayerich,David;Dickinson,MaryE;Larin,KirillV
• 通讯作者: Larin,KirillV

Biomechanical assessment of myocardial infarction using optical coherence elastography.

• DOI: 10.1364/boe.9.000728
• 发表时间: 2018-02
• 期刊: Biomedical optics express
• 影响因子: 3.4
• 作者: Shang Wang;Manmohan Singh;Thuy Tien Tran;John P. Leach;S. Aglyamov;I. Larina;James F. Martin;K. Larin

Prolonged in vivo functional assessment of the mouse oviduct using optical coherence tomography through a dorsal imaging window.

使用光学相干断层扫描通过背侧成像窗口对小鼠输卵管进行长期体内功能评估。

• DOI: 10.1002/jbio.201700316
• 发表时间: 2018
• 期刊: Journal of biophotonics
• 影响因子: 2.8
• 作者: Wang,Shang;Syed,Riana;Grishina,OlgaA;Larina,IrinaV
• 通讯作者: Larina,IrinaV

Comparison and combination of rotational imaging optical coherence tomography and selective plane illumination microscopy for embryonic study.

• DOI: 10.1364/boe.8.004629
• 发表时间: 2017-09
• 期刊: Biomedical optics express
• 影响因子: 3.4
• 作者: Chen Wu;Henry Le;Shihao Ran;Manmohan Singh;I. Larina;D. Mayerich;M. Dickinson;K. Larin