Role of hemodynamics and ErbB signaling in cardiac trabeculation

项目摘要/摘要 这份提案描述了一项为期五年的职业发展计划，其目标是为博士做好准备。 刘建东要求担任独立调查员。这个项目将促进他的事业 通过提供分子和发育心脏生物学方面的专业知识来促进心脏发育。这个 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的生物物理学。他是心脏方面的专家 发展，并在培训独立科学家方面有着长期的记录。培训计划 包括与咨询委员会的有组织的指导、正式的课程作业和研究 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用于 研究斑马鱼的心脏形态发生。他使用这些工具来探索 心脏小梁形成中的血流动力学和ErbB信号，这是一个关键的形态发生过程， 优化心脏内部结构，有效传导和收缩。 这项工作表明：1)骨小梁形成的启动受血液流动的调节 可能需要Notch信号的过程，以及2)ErbB2细胞自主调节 心肌细胞迁移形成心脏小梁。在研究提案中，建东博士将 以这些发现为基础来检验以下假设：(1)血流激活Notch信号 诱导心内膜神经调节蛋白1(NRG1)的表达，以及(2)NRG1激活其ErbB 心肌中的受体通过引起心肌细胞心尖来启动小梁形成 收缩。他将首先仔细评估细胞结构、细胞形状变化和细胞 在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，以确定 将流动和剪切力与长期结构变化联系起来的调控网络 心脏，这是一个对理解两种发育障碍至关重要的区域 心脏形成以及多种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的研究奠定了基础 当他成为一名独立调查员。

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.