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.

项目总结/摘要 整合成像和计算以表征心肌发育中的神经嵴细胞 和再生 心脏神经嵴细胞是一群从神经管中出现的高度迁移的细胞， 通过咽弓与发育中的心脏融合最近的进展表明， 一种新的神经嵴细胞亚群具有整合到心腔中并分化的能力 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 心室腔发育过程中的分化。尽管在过去几十年中获得了知识， 神经嵴来源的心肌细胞对收缩功能的贡献和这些心肌细胞的作用 在Notch中，信号传导介导心室重构仍然是难以捉摸的。斑马鱼胚胎中的小心脏 新生小鼠也阻碍了精确的心脏结构和功能评估。基于这些原因，我寻求 将我们先进的成像技术（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，DIAMOND），以表征 神经嵴源性心肌细胞对心肌发育的结构和功能贡献 和高时空分辨率的再生。在宗熙艾教授的共同指导下， （机械传导，加州大学洛杉矶分校）、陈兆年教授（发育生物学，加州大学洛杉矶分校）和德彪教授 李（磁共振成像，雪松-西奈医学中心），我将继续与教授敦中野合作 （发育生物学，UCLA）和Adam Langenbacher博士（发育生物学，UCLA），并咨询 Joseph Wu教授（心脏干细胞，斯坦福大学），Sandra Rugonyi教授（俄勒冈州健康与科学 大学），琳达德默尔教授（血管生物学，加州大学洛杉矶分校）来验证我们的假设。我们假设， 嵴细胞对心室肌有贡献，而神经嵴衍生的心肌细胞对于 收缩功能和心室修复。为了验证这个假设，我们有三个目标。在目标1中，我们 通过SV-LSFM阐明心脏神经嵴细胞的4-D迁移路径。在目标2中，我们将演示4-D 心脏神经嵴细胞通过DIAMOND对心室肌的贡献后的结构和功能。 在目标3中，我将独立量化神经嵴源性消融后的心室修复 心肌细胞和小鼠模型。在这方面，我们认为， 遗传模型与先进成像和计算的集成将提供新的机械和 神经嵴细胞对收缩功能和心室修复作用的发育学研究 在Notch信号通路的调控下。