Mechanism Shaping the Adhesion Landscape During Spinal Cord Development

脊髓发育过程中粘附景观的形成机制

• 批准号: 10319256
• 负责人: Tony Yu-Chen Tsai
• 金额: $ 24.9万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319256
• 关键词: 3-Dimensional; Address; Adhesions; Affect; Area; Biological Assay; Cell Adhesion; Cell Adhesion Molecules; Cell Fate Control; Cell Separation; Cells; Collaborations; Complement; Computer Models; Development; Developmental Biology; Dorsal; Down-Regulation; E-Cadherin; Embryo; Embryonic Development; Ensure; Event; Exhibits; Gene Expression; Gene Family; Genes; Genetic; Genetic Engineering; Genetic Screening; Genetic Transcription; Goals; Grant; Image; Image Analysis; Individual; Institutes; Interdisciplinary Study; Knowledge; Learning; Measurement; Measures; Mechanics; Mediating; Mediator of activation protein; Mentors; Mentorship; Methods; Modeling; Molecular; Morphogenesis; N-Cadherin; Neural Tube Development; Neural tube; Optics; Paper; Participant; Pattern; Pattern Formation; Phase; Positioning Attribute; Process; Publications; Publishing; Regulation; Regulator Genes; Research; Resolution; Role; Series; Shapes; Side; Signal Transduction; Snails; Sorting - Cell Movement; Specific qualifier value; Spinal Cord; Techniques; Tissues; Training; Up-Regulation; Writing; Zebrafish; base; biophysical techniques; career; cell determination; cell fate specification; cell motility; cell type; computer framework; differential expression; experience; genetic approach; graduate student; in vivo; migration; mutant; nerve stem cell; neural patterning; novel; post-doctoral training; programs; skills; spatiotemporal; student mentoring; success; symposium; three-dimensional modeling; tool

PROJECT SUMMARY An important question in developmental biology is how cell fate specification and cell movement are coordinated during tissue morphogenesis to ensure all cell types reach their desired positions properly. One example of this elegant coordination is the patterning of neural progenitors in the zebrafish spinal cord. In this proposal, I will combine biophysical and genetic approaches to understand how cell fate specification and cell adhesion are coordinated in the zebrafish neural tube. Studies from my early postdoctoral training have identified E-cadherin (Cdh1), N-cadherin (Cdh2), and their transcriptional regulators as critical mediators for patterning of neural progenitor domains. Building on these initial findings, this proposal aims to obtain a multi- scale understanding of spinal cord pattern formation from the differential adhesion forces mediated by Cdh1 and Cdh2 in different neural progenitor cell types (Aim1), to the gene regulatory network controlling the spatial patterns of Cdh1 and Cdh2 expressions (Aim2), to a computational framework to simulate cell sorting at the tissue scale (Aim1). The experimental platform established in Aims 1 and 2 will be used to characterize novel regulators of cell adhesion dynamics during spinal cord pattern formation and morphogenesis (Aim 3). This proposal will combine my analytical skills developed as a graduate student to analyze spatiotemporal dynamics of adhesion molecules at cellular and subcellular levels, the experimental knowledge acquired during my early postdoctoral training to genetically engineer zebrafish and image live embryos with single cell resolution, and the proposed training during the K99 mentored phase to probe cell mechanics and optically perturb gene expression at high spatiotemporal precision. The training during the K99 mentored phase will integrate the expertise of all four of my co-mentors and will complement my past training to form a complete research program in my own independent lab to measure, perturb, and model spatiotemporal dynamics of adhesion molecules in neural progenitor cells during spinal cord development. My plan for transitioning to independence include professional trainings from all four of my co-mentors to mentor students, manage labs, write grants, publish papers, present research results in conferences, and establish scientific collaborations. By learning and interacting with all four co-mentors in different academic institutes, I will combine their strength to formulate my own lab culture and mentoring style. My long-term career goal is to direct a multidisciplinary research program studying the control of spatiotemporal dynamics of cellular and subcellular events underlying robust embryo development. So far I have achieved significant progress towards this goal in the form of research experience, successful publications, and initiation of collaborations. I firmly believe, however, that a K99 mentored phase will help maximize my chances for success by providing access to additional mentorship and training that would be otherwise lacking from my current postdoctoral experience.

项目总结 发育生物学中的一个重要问题是细胞命运的指定和细胞运动是如何 在组织形态发生过程中进行协调，以确保所有类型的细胞正确地达到其所需的位置。一 这种优雅协调的例子是斑马鱼脊髓中神经前体细胞的模式。在这 提案中，我将结合生物物理学和遗传学的方法来了解细胞命运规范和细胞 在斑马鱼的神经管中，黏附是协调的。我早期博士后培训的研究成果 发现E-钙粘蛋白(CDH1)、N-钙粘蛋白(CDH2)及其转录调节因子是 神经前体结构域的图案化。在这些初步调查结果的基础上，这项提案旨在获得多个 从CDH1介导的不同粘附力对脊髓模式形成的尺度理解 和cdh2在不同的神经前体细胞类型(Aim1)中，对控制空间的基因调控网络 CDH1和CDH2表达式的模式(AIM2)，到一个计算框架，以在 组织规模(Aim1)。在AIMS 1和AIMS 2中建立的实验平台将用于表征小说 脊髓形态形成和形态发生过程中细胞黏附动态的调节(目标3)。 这项提议将结合我作为研究生培养的分析技能来分析时空 黏附分子在细胞和亚细胞水平上的动力学，在 我早年接受的博士后培训是通过基因工程改造斑马鱼，并用单细胞成像活胚胎 解决方案，以及在K99指导阶段进行的拟议培训，以探测细胞力学和光学 高时空精确度的扰动基因表达。K99指导阶段的培训将 整合我所有四位合作导师的专业知识，并将与我过去的培训相辅相成，形成完整的 在我自己的独立实验室中进行的研究计划，以测量、扰动和模拟 脊髓发育过程中神经前体细胞中的黏附分子。 我过渡到独立的计划包括我所有四位共同导师的专业培训 指导学生，管理实验室，写助学金，发表论文，在会议上展示研究成果，以及 建立科学合作关系。通过与所有四位不同学术领域的合作导师学习和互动 研究所，我会结合他们的力量，形成我自己的实验室文化和指导风格。 我的长期职业目标是指导一个多学科的研究项目，研究对 支持强健胚胎发育的细胞和亚细胞事件的时空动力学。到目前为止我 以研究经验的形式朝着这一目标取得了重大进展，成功 出版物，以及启动合作。然而，我坚信K99指导阶段会有所帮助 通过提供额外的指导和培训，最大限度地提高我的成功机会 否则从我目前的博士后经验来看是缺乏的。