Role of hemodynamics and ErbB signaling in cardiac trabeculation

描述（由申请人提供）：该提案描述了一个为期五年的职业发展计划，其目标是培养刘建东博士成为一名独立研究者。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、加州大学旧金山分校生物化学与生物物理学教授Didier Stainier博士提供。他是心脏发育方面的专家，在培养独立科学家方面有着悠久的历史。培训计划包括一个咨询委员会的结构化指导、正式课程和一个研究项目，该项目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信号在心脏小梁中的作用，心脏小梁是优化心室内部结构以实现有效传导和收缩的关键形态发生过程。这项工作证明了1)小梁的启动是由血流调节的，这一过程可能需要Notch信号传导，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，建冬博士将以这些发现为基础，验证以下假设：(1)血流激活Notch信号诱导心内膜中神经调节蛋白1 （nrg1）的表达；(2)nrg1激活其在心肌中的ErbB受体，通过引起心肌细胞顶端收缩来启动小梁。他将开始仔细评估细胞结构，细胞形状的变化和细胞迁移在心脏小梁。然后，他将进行详细的功能研究，以定义将血流和剪切应力与心脏长期结构变化联系起来的调节网络，这是一个对理解心脏形成的发育障碍以及许多形式的获得性心脏病具有根本重要性的领域。此外，本工作将为建东博士成为独立研究者后开展心脏小梁的进一步研究奠定基础。

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.