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

基本信息

批准号：
10203220
负责人：
Yichen Ding
金额：
$ 24.66万
依托单位：
UNIVERSITY OF TEXAS DALLAS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-04 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203220
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 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 stem cells virtual reality

项目摘要

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 /摘要整合成像和计算以表征心肌发育中的神经rest细胞和再生心脏神经rest细胞是从神经管中出现的高度迁移细胞的群体，迁移通过咽弓并整合到发育中的心脏中。最近的进步表明神经rest细胞的新亚种群具有整合到心脏腔中并分化的能力进入斑马鱼和小鼠的心肌细胞。 Notch信号传导调节心肌细胞的增殖和心室发育过程中的分化。尽管过去几十年中获得了知识，但神经rest衍生的心肌细胞对收缩功能的贡献以及这些心肌细胞的作用在Notch信号传导介导的心室重塑中仍然难以捉摸。斑马鱼胚胎中的小心脏大小新生儿小鼠还阻碍了精确的心脏结构和功能评估。由于这些原因，我寻求为了整合我们的高级成像（亚素分辨率灯页荧光显微镜，SV-LSFM）计算（心肌机械变形的位移分析，钻石）以表征神经衍生的心肌细胞对心肌发育的结构和功能贡献并具有高时空分辨率的再生。在Tzung Hsiai教授的联合指导下（加州大学洛杉矶分校的机械转移），Jau-Nian Chen教授（加州大学洛杉矶分校的发展生物学）和Debiao教授李（雪松锡奈医学中心的成像先生），我将继续与nakano教授合作（发育生物学，加州大学洛杉矶分校）和亚当·兰肯巴赫（Adam Langenbacher）博士（加州大学洛杉矶分校的发展生物学），并咨询 Joseph Wu教授（Stanford心脏干细胞），Sandra Rugonyi教授（俄勒冈州健康与科学大学），琳达·德默（Linda Demer）教授（UCLA血管生物学），以检验我们的假设。我们假设该神经波峰细胞有助于心室心肌和神经rest衍生的心肌细胞对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AIM 1中，我们将通过SV-LSFM阐明心脏神经rest细胞的4-D迁移路径。在AIM 2中，我们将展示4-D 通过钻石对心室心肌的心脏神经rest细胞贡献后的结构和功能。在AIM 3中，我将在消融神经rest衍生后独立量化心室修复斑马鱼和小鼠模型中的心肌细胞与我的合作者。在这种情况下，我们相信遗传模型与高级成像和计算的整合将提供新的机械和对神经rest细胞对收缩功能和心室修复的贡献的发展见解在Notch信号通路的调节下。