Role of hemodynamics and ErbB signaling in cardiac trabeculation

描述（由申请人提供）：本提案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担任独立研究者做好准备。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 Escherier博士，加州大学弗朗西斯科分校生物化学和生物物理学教授提供。他是心脏发育方面的专家，长期以来一直在培训独立的科学家。培训计划包括与咨询委员会，正式课程和研究计划，这将提供分子和发育心脏生物学的全面培训结构化的导师。在他的初步研究中，Jiandong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液动力学和ErbB信号在心脏小梁形成中的作用，这是一个关键的形态发生过程，优化了心室的内部结构，以实现有效的传导和收缩。这项工作已经证明：1）小梁形成的起始在可能需要Notch信号传导的过程中受到血流的调节，以及2）ErbB2细胞自主调节心肌细胞迁移以形成心脏小梁。在研究计划中，Jiandong博士将基于这些发现来验证以下假设：（1）血流激活Notch信号传导诱导内皮细胞中的神经调节蛋白1（nrg 1）表达，以及（2）Nrg 1激活心肌中的ErbB受体，通过引起心肌细胞顶端收缩来启动小梁形成。他将开始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，这是一个对于理解心脏形成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，这项工作将为Jiandong博士成为独立研究者后开展的心脏小梁形成研究奠定基础。 公共卫生相关性：在胚胎发生期间，小梁形成或致密化的失败导致先天性心肌病，而在许多形式的获得性心脏病中，心室变得不利地重塑，丧失正常的心室小梁结构，从而导致心室功能恶化。这项建议的目的是描绘潜在的心脏小梁形成的调节机制，以提高对心脏疾病的理解，并促进治疗的搜索。

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. PUBLIC HEALTH RELEVANCE: Failure of trabecular formation or compaction during embryogenesis causes congenital cardiomyopathy, while in many forms of acquired heart disease, the ventricle becomes adversely remodeled, with loss of normal ventricular trabecular structure and consequent deterioration of ventricular function. This proposal aims to delineate regulatory mechanisms underlying cardiac trabeculation to improve understanding of cardiac disease and facilitate the search for treatments.