Role of hemodynamics and ErbB signaling in cardiac trabeculation

描述(由申请人提供)：本建议书描述了一个为期五年的职业发展计划，其目标是为刘建东博士作为一名独立研究员的角色做好准备。该计划将通过提供分子和发育心脏生物学方面的专业知识来促进他的职业发展。主要指导将由导师Didier Stainier博士提供，他是加州大学旧金山分校的生物化学和生物物理学教授。他是心脏开发方面的专家，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结构化指导，正式的课程安排，以及将提供分子和发育心脏生物学方面的全面培训的研究计划。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心脏形态发生的工具。他使用这些工具来探索血流动力学和ErbB信号在心脏小梁形成中的作用，这是一种关键的形态发生过程，可以优化心室室的内部结构，以实现有效的传导和收缩。这项工作表明：1)在可能需要Notch信号的过程中，血流调节小梁的启动；2)ErbB2细胞自主调节心肌细胞迁移形成心脏小梁。在这项研究提案中，建东博士将以这些发现为基础，检验以下假设：(1)血流激活Notch信号会诱导心内膜中NeuRegin1(NRG1)的表达，以及(2)Nrg1激活心肌中的ErbB受体，通过导致心肌细胞心尖收缩来启动小梁形成。他将首先仔细评估心脏小梁形成过程中的细胞结构、细胞形状变化和细胞迁移。然后，他将进行详细的功能研究，以确定将流动和切应力与心脏长期结构变化联系起来的调节网络，这一区域对于了解心脏形成的发育障碍以及许多形式的获得性心脏病都是至关重要的。此外，这项工作将为建东博士成为独立研究员后开展的未来心脏小梁研究提供基础。

DESCRIPTION (provided by applicant): 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.