Integrating imaging and computation to characterize neural crest cells in the myocardial development and regeneration

整合成像和计算来表征心肌发育和再生中的神经嵴细胞

• 批准号: 9806864
• 负责人: Yichen Ding
• 金额: $ 11.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-05 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806864
• 关键词: 3-Dimensional; Ablation; Animal Genetics; Animal Model; Architecture; Biology; Blood Vessels; Branchial arch structure; Cardiac; Cardiac Myocytes; Cells; Collaborations; Consult; Defect; Development; Developmental Biology; Diastole; Diphtheria Toxin; Dominant-Negative Mutation; Doxorubicin; Embryo; Fishes; Fluorescence Microscopy; Genetic Engineering; Genetic Models; Goals; Health Sciences; Heart; Heart Abnormalities; Heart Injuries; Heterogeneity; Image; Joints; Knowledge; Light; Literature; Magnetic Resonance Imaging; Mechanics; Mediating; Medical center; Mentorship; Messenger RNA; Modeling; Mus; Myocardial; Myocardium; Natural regeneration; Neonatal; Neural Crest; Neural Crest Cell; Neural tube; Notch Signaling Pathway; Oregon; Periodicals; Phase; Phenotype; Physiological; Population; Recovery of Function; Regulation; Resolution; Role; Signal Transduction; Stem cells; Structure; Systole; Techniques; Testing; Tracer; Transgenic Animals; Transgenic Model; Transgenic Organisms; Universities; Ventricular; Ventricular Remodeling; Zebrafish; base; congenital heart disorder; fluorescence microscope; heart dimension/size; image processing; improved; insight; mechanotransduction; migration; mouse model; mutant; neural network; notch protein; overexpression; professor; repaired; restoration; septal defect; spatiotemporal; virtual reality

Project Summary / Abstract Integrating imaging and computation to characterize neural crest cells in the myocardial development and regeneration Cardiac neural crest cells are a population of highly migratory cells emerging from the neural tube, migrating through the pharyngeal arches and integrating into the developing heart. Recent advances demonstrate that a new sub-population of neural crest cells has the capacity to integrate into the cardiac chamber and differentiate into cardiomyocytes in both zebrafish and mice. Notch signaling regulates cardiomyocyte proliferation and differentiation during ventricular chamber development. Despite the knowledge gained in the past decades, the contribution of neural crest-derived cardiomyocytes to contractile function and the role of these cardiomyocytes in Notch signaling-mediated ventricular remodeling remain elusive. The small heart size in zebrafish embryos and neonatal mice also hinders precise cardiac structural and functional assessment. For these reasons, I seek to integrate our advanced imaging (sub-voxel resolution light-sheet fluorescence microscopy, SV-LSFM) with computation (displacement analysis of myocardial mechanical deformation, DIAMOND) to characterize the structural and functional contributions of the neural crest-derived cardiomyocytes to the myocardial development and regeneration with high spatiotemporal resolution. Under the joint mentorship from Professor Tzung Hsiai (Mechanotransduction, UCLA), Professor Jau-Nian Chen (Developmental biology, UCLA) and Professor Debiao Li (MR imaging, Cedars-Sinai Medical Center), I will continue to collaborate with Professor Atsushi Nakano (Developmental biology, UCLA) and Dr. Adam Langenbacher (Developmental biology, UCLA), and consult with Professor Joseph Wu (Cardiac stem cells, Stanford), Professor Sandra Rugonyi (Oregon Health & Science University), Professor Linda Demer (Vascular biology, UCLA) to test our hypothesis. We hypothesize that neural crest cells contribute to the ventricular myocardium and neural crest-derived cardiomyocytes are essential for the contractile function and ventricular repair. To test this hypothesis, we will have three aims. In Aim 1, we will elucidate the 4-D migration path of cardiac neural crest cell via SV-LSFM. In Aim 2, we will demonstrate 4-D structure and function following cardiac neural crest cell contribution to the ventricular myocardium via DIAMOND. In Aim 3, I will independently quantify the ventricular repair following the ablation of neural crest-derived cardiomyocytes in zebrafish and mouse models with my collaborators. In this context, we believe that the integration of genetic models with advanced imaging and computation will provide new mechanical and developmental insights into the contribution of neural crest cells to contractile function and ventricular repair under the regulation of Notch signaling pathway.

项目摘要/摘要 心肌发育过程中神经脊细胞的成像与计算相结合 和再生 心脏神经脊细胞是从神经管中涌出的一群高度迁移的细胞，迁移 穿过咽弓，融入发育中的心脏。最近的进展表明， 新的神经脊细胞亚群具有整合到心腔并分化的能力 转化为斑马鱼和小鼠的心肌细胞。Notch信号调节心肌细胞增殖和 脑室发育过程中的分化。尽管在过去的几十年里获得了一些知识，但 神经沟来源的心肌细胞对收缩功能的贡献及其作用 在Notch中，信号介导的心室重构仍然难以捉摸。斑马鱼胚胎的小心脏尺寸 而新生小鼠也阻碍了准确的心脏结构和功能评估。出于这些原因，我寻求 将我们的先进成像技术(亚体素分辨率光片荧光显微镜，SV-LSFM)与 计算(心肌机械变形的位移分析，钻石)来表征 神经沟来源的心肌细胞对心肌发育的结构和功能贡献 以及具有高时空分辨率的再生。在宗雄教授的共同指导下 (加州大学洛杉矶分校机械转导)、加州大学洛杉矶分校发育生物学陈昭年教授和德标教授 李(雪松西奈医学中心MR成像)，我将继续与中野敦教授合作 (发展生物学，UCLA)和Adam Langenbacher博士(发展生物学，UCLA)，并咨询 Joseph Wu教授(斯坦福大学心脏干细胞)，Sandra Rugonyi教授(俄勒冈州健康与科学) 加州大学洛杉矶分校血管生物学教授琳达·德默(Linda Demer)验证了我们的假设。我们假设神经 CREST细胞参与了心肌的发育，而来源于CREST的神经细胞是心肌细胞的重要组成部分 收缩功能和心室修复。为了检验这一假设，我们将有三个目标。在目标1中，我们将 通过SV-LSFM阐明心脏神经脊细胞的4-D迁移路径。在目标2中，我们将演示4-D 心脏神经脊细胞通过钻石对心室肌的贡献 在目标3中，我将独立地量化消融术后的脑室修复。 斑马鱼和小鼠模型中的心肌细胞。在这方面，我们认为 将遗传模型与先进的成像和计算相结合将提供新的机械和 神经脊细胞对收缩功能和心室修复作用的发育研究 在Notch信号通路的调控下。