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

• 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
• 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

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.

项目摘要/摘要 该建议描述了一个五年的职业发展计划，其目标是为博士做准备。 若东刘（Jiandong Liu）担任独立研究员的角色。该计划将促进他的职业生涯 通过提供分子和发育性心脏生物学方面的专业知识来发展。这 主要指导将由导师，生物化学教授Didier Stainier博士提供 ＆生物物理学在加利福尼亚大学旧金山分校。他是心脏的专家 发展，并有培训独立科学家的悠久记录。培训计划 包括与咨询委员会的结构化指导，正式课程和研究 计划将提供分子和发育性心脏生物学的彻底培训。 在他的初步研究中，Jiandong博士开发并验证了一套用于使用的工具 研究斑马鱼中的心脏形态发生。他使用这些工具来探索 心脏小梁中的血液动力学和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，以有效传导和收缩。 这项工作表明1）小偷的开始受到A中的血流调节 可能需要Notch信号的过程，2）ERBB2细胞自主调节 心肌细胞迁移以形成心脏小梁。在研究建议中，Jiandong博士将 基于这些发现以检验（1）血流激活Notch信号的假设 诱导内膜中诱导Neuregulin1（NRG1）表达，（2）NRG1激活其ERBB 心肌中的受体通过引起心肌细胞来启动小梁 收缩。他将首先仔细评估细胞结构，细胞形状变化和细胞 心脏小偷期间的迁移。然后，他将进行详细的功能研究以定义 将流动和剪切应力与长期结构变化联系起来的监管网络 心脏，对于理解两种发育障碍的基本重要性 心脏形成以及多种形式的心脏病。此外，这项工作将 为未来的关于心脏小梁的研究提供了基础 当他成为独立调查员时。