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.

项目摘要 发育生物学的一个重要问题是细胞命运规格和细胞运动如何 在组织形态发生过程中协调，以确保所有细胞类型都正确地达到所需的位置。一 这种优雅协调的例子是斑马鱼脊髓中神经祖细胞的图案。在这个 提案，我将结合生物物理和遗传方法，以了解细胞命运规格和细胞 在斑马鱼神经管中协调粘附。我早期的博士后培训的研究有 确定的E-钙粘蛋白（CDH1），N-钙粘蛋白（CDH2）及其转录调节剂作为关键介体 神经祖细胞域的模式。在这些初步发现的基础上，该提案旨在获得多种 从CDH1介导的差分粘附力对脊髓模式形成的比例理解 以及不同神经祖细胞类型（AIM1）的CDH2，控制空间的基因调节网络 CDH1和CDH2表达式的模式（AIM2），用于模拟细胞分类的计算框架 组织量表（AIM1）。 AIMS 1和2中建立的实验平台将用于表征新颖 脊髓模式形成和形态发生过程中细胞粘附动力学的调节剂（AIM 3）。 该建议将结合我作为研究生开发的分析技能来分析时空 粘附分子在细胞和亚细胞水平上的动力学，在期间获得的实验知识 我早期的博士后培训对基因工程斑马鱼和带有单细胞的现场胚胎 分辨率，以及K99指导阶段的拟议训练，以探测细胞力学和光学 在高时空精度下的扰动基因表达。 K99指导阶段的培训将 整合我所有四个联合主机的专业知识，并将补充我过去的培训以形成完整的培训 我自己的独立实验室中的研究计划，以测量，扰动和模型的时空动力学 脊髓发育过程中神经祖细胞中的粘附分子。 我向独立过渡的计划包括从我所有四个联合给出者到的专业培训 指导学生，管理实验室，撰写赠款，发表论文，在会议中进行研究结果以及 建立科学合作。通过学习和与不同学术的所有四个联合官员进行互动 研究所，我将结合他们的力量来制定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项多学科研究计划，以研究对 稳健胚胎发育的基础细胞和亚细胞事件的时空动力学。到目前为止 以研究经验的形式取得了重大进展，成功 出版物和合作的启动。但是，我坚信K99的指导阶段将有所帮助 通过提供获得其他指导和培训的机会，最大程度地利用了我的成功机会 否则，由于我目前的博士后经验缺乏。