Role of hemodynamics and ErbB signaling in cardiac trabeculation

项目总结/摘要 该计划描述了一个为期五年的职业发展计划，其目标是培养博士。 刘建东先生获委任为独立调查员。这个节目将促进他的事业 通过提供分子和发育心脏生物学方面的专业知识，的 主要指导将由导师，Didier Escherier博士，生物化学教授 加州大学旧金山分校弗朗西斯科生物物理学系。他是心脏病专家 该公司在开发和培训独立科学家方面有着悠久的记录。培训计划 包括结构化的指导与咨询委员会，正式的课程，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，Jiandong博士开发并验证了一套工具， 研究斑马鱼心脏形态发生。他使用这些工具来探索 心脏小梁形成是一个重要的形态发生过程， 优化心室的内部结构，以实现有效的传导和收缩。 这项工作表明：1）小梁形成的起始受血液流动的调节， 可能需要Notch信号传导的过程，以及2）ErbB 2细胞自主调节 心肌细胞迁移以形成心脏小梁。在研究提案中，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 诱导神经调节蛋白1（nrg 1）在内皮细胞中的表达;（2）Nrg 1激活其ErbB 受体，通过引起心肌细胞顶端 收缩。他将开始仔细评估细胞结构，细胞形状的变化和细胞 在心脏小梁形成过程中迁移。然后，他将进行详细的功能研究， 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，一个对理解发育障碍和 心脏形成以及许多形式的后天性心脏病。此外，这项工作将 为Jiandong博士今后开展心脏小梁形成的研究奠定了基础 当他成为独立调查员的时候

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.