Role of hemodynamics and ErbB signaling in cardiac trabeculation

血流动力学和 ErbB 信号在心脏小梁形成中的作用

基本信息

批准号：
8626437
负责人：
Jiandong Liu
金额：
$ 24.4万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8626437
关键词：
Advisory Committees Apical Architecture Area Biochemistry Biological Models Biology Biophysics Blood flow California Cardiac Cardiac Myocytes Cardiomyopathies Cell Shape Cell physiology Cells Complex Data Deterioration Development Due Process Embryonic Development Endocardium Event Exhibits Failure Foundations Future Genetic Goals Heart Heart Diseases Heart Ventricle Link Mediating Mentors Mentorship Modeling Molecular Morphogenesis Myocardial Myocardium Pathway interactions Process Research Research Personnel Research Proposals Resolution Role San Francisco Scientist Shapes Signal Pathway Signal Transduction Structure Testing Time Training Universities Ventricular Ventricular Function Work Zebrafish abstracting career development cell motility constriction developmental disease hemodynamics improved migration muscular structure notch protein professor programs receptor response shear stress spatiotemporal tool

项目摘要

Project Summary/Abstract This proposal describes a five-year career development program whose goal is to prepare Dr. Jiandong Liu for a role as an independent investigator. This program will promote his career development by providing expertise in molecular and developmental cardiac biology. The principal guidance will be provided by the mentor, Dr. Didier Stainier, Professor of Biochemistry & Biophysics at the University of California, San Francisco. He is an expert in cardiac development and has a long record of training independent scientists. The training plan includes structured mentorship with an advisory committee, formal coursework, and a research program which will provide thorough training in molecular and developmental cardiac biology. In his preliminary studies, Dr. Jiandong has developed and validated a set of tools to be used to study cardiac morphogenesis in zebrafish. He has used these tools to explore the role for hemodynamic and ErbB signaling in cardiac trabeculation, a critical morphogenetic process that optimizes the internal structure of the cardiac ventricle for efficient conduction and contraction. This work has demonstrated 1) that the initiation of trabeculation is regulated by blood flow in a process that likely requires Notch signaling, and 2) ErbB2 cell-autonomously regulates cardiomyocyte migration to form cardiac trabeculae. In the research proposal, Dr. Jiandong will build on these findings to test the hypotheses that (1) activation of Notch signaling by blood flow induces neuregulin1 (nrg1) expression in the endocardium, and (2) Nrg1 activates its ErbB receptors in the myocardium to initiate trabeculation by causing cardiomyocyte apical constriction. He will begin by carefully assessing cell architecture, cell shape changes and cell migration during cardiac trabeculation. He will then perform detailed functional studies to define the regulatory networks that link flow and shear stress to long-term structural changes in the heart, an area of fundamental importance for understanding both developmental disorders of heart formation as well as many forms of acquired heart disease. In addition, this work will provide a foundation for future studies on cardiac trabeculation to be carried out by Dr. Jiandong when he becomes an independent investigator.

项目概要/摘要该提案描述了一个为期五年的职业发展计划，其目标是为博士做好准备。刘建东担任独立调查员。这个计划将促进他的职业生涯通过提供分子和发育心脏生物学方面的专业知识来开发。这主要指导将由导师生物化学教授 Didier Stainier 博士提供＆加州大学旧金山分校生物物理学。他是心脏病方面的专家发展并拥有培养独立科学家的长期记录。培训计划包括咨询委员会的结构化指导、正式课程和研究该计划将提供分子和发育心脏生物学方面的全面培训。在他的初步研究中，建东博士开发并验证了一套工具，用于研究斑马鱼的心脏形态发生。他使用这些工具来探索这个角色心脏小梁形成中的血流动力学和 ErbB 信号传导，这是一个关键的形态发生过程优化心室的内部结构，以实现有效的传导和收缩。这项工作证明了 1) 小梁形成的起始是由血管中的血流调节的。可能需要 Notch 信号传导的过程，以及 2) ErbB2 细胞自主调节心肌细胞迁移形成心脏小梁。在研究计划中，建东博士将基于这些发现来检验以下假设：(1) 血流激活 Notch 信号传导诱导心内膜中神经调节蛋白 1 (nrg1) 的表达，并且 (2) Nrg1 激活其 ErbB 心肌中的受体通过引起心肌细胞顶端来启动小梁形成收缩。他将首先仔细评估细胞结构、细胞形状变化和细胞心脏小梁形成过程中的迁移。然后他将进行详细的功能研究来定义将流动和剪切应力与长期结构变化联系起来的调节网络心脏，对于理解发育障碍至关重要的领域心脏形成以及许多形式的获得性心脏病。此外，这项工作将为建东博士今后开展心脏小梁研究奠定基础当他成为一名独立调查员时。