Role of hemodynamics and ErbB signaling in cardiac trabeculation

血流动力学和 ErbB 信号在心脏小梁形成中的作用

• 批准号: 8306031
• 负责人: Jiandong Liu
• 金额: $ 8.87万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306031
• 关键词: Advisory Committees; Apical; Architecture; Area; Biochemistry; Biological Models; Biology; Biophysics; Blood flow; California; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Shape; Cell physiology; Cells; Complex; Data; Deterioration; Development; Due Process; Embryonic Development; Endocardium; Event; Exhibits; Failure; Foundations; Future; Genetic; Goals; Heart; Heart Diseases; Heart Ventricle; Link; Mediating; Mentors; Mentorship; Modeling; Molecular; Morphogenesis; Myocardial; Myocardium; Pathway interactions; Process; Research; Research Personnel; Research Proposals; Resolution; Role; San Francisco; Scientist; Shapes; Signal Pathway; Signal Transduction; Structure; Testing; Time; Training; Universities; Ventricular; Ventricular Function; Work; Zebrafish; career development; cell motility; constriction; developmental disease; hemodynamics; improved; migration; muscular structure; notch protein; professor; programs; receptor; response; shear stress; spatiotemporal; tool

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.

描述（由申请人提供）：该提案描述了一项五年的职业发展计划，其目标是为Jiandong Liu博士做好准备，以担任独立研究员。该计划将通过提供分子和发育性心脏生物学专业知识来促进他的职业发展。主要的指导将由导师Didier Stainier博士，旧金山分校生物化学与生物物理学教授Didier Stainier博士提供。他是心脏发展方面的专家，并且在培训独立科学家方面有很长的记录。培训计划包括与咨询委员会的结构化指导，正式课程和研究计划，该计划将提供有关分子和发育性心脏生物学的彻底培训。在他的初步研究中，Jiandong博士开发并验证了一组用于研究斑马鱼中心脏形态发生的工具。他已经使用这些工具来探索心脏小梁中血液动力学和ERBB信号传导的作用，这是一种关键的形态发生过程，可优化心脏的内部结构，以有效地传导和收缩。这项工作表明1）在可能需要凹口信号的过程中，小梁的启动受血流调节，而2）ERBB2细胞自动调节心肌细胞迁移以形成心脏小径。 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.他将首先仔细评估细胞结构，细胞形状的变化和心脏小偷期间的细胞迁移。然后，他将进行详细的功能研究，以定义将流动和剪切应力与心脏的长期结构变化联系起来的调节网络，这对于理解心脏形成的发育障碍以及许多形式的心脏病的发展障碍至关重要。此外，这项工作将为未来的关于心脏小梁的研究基础，当时江博士成为一名独立研究员时，将由他进行。