CAREER:Integrative Analysis for Reverse Engineering Embryonic Pattern Repair Mechanisms

揭示发育中的组织如何能够自我修复，对于设计治疗先天缺陷或组织退行性疾病的新策略至关重要。NSF CAREER计划的目标是建立一个跨学科的研究-教育-推广计划，该计划基于三个方面：(i)对组织生长和稳态控制机制的定量、系统级分析；（ii）培养具有发育生物学和组织工程学基础的化学工程师和生物工程师；（三）在当地社区拓展，从代表性不足的背景中招收科学和工程专业的学生。特别是，该项目旨在显著扩展我们对胚胎如何能够纠正组织形成过程中指定细胞类型相对空间分布的早期错误的理解。对模式修复过程中细胞信号传导和机制的深入了解可以为合成生物学的应用提供信息，包括设计在空间和时间上操纵细胞决策过程的方法。本职业建议的总体目标是建立一个综合的研究-教育-推广计划，从工程的角度发展和教授系统生物学方法。特别是，该项目旨在显著扩展我们对胚胎如何能够纠正组织形成过程中指定细胞类型相对空间分布的早期错误的理解。当受到环境变化或遗传缺陷的影响时，胚胎表现出显著的修复模式缺陷的能力。识别修复组织的控制系统对于理解先天缺陷的潜在原因以及由于生长失调而发生的疾病非常重要。该项目将产生新的成像方法、用于组织模式修复遗传模型系统、果蝇（Drosophila melanogaster）生成的多路图像数据的开源数据分析工具，以及广泛适用于组织微环境维持研究的模拟资源。PI的团队将测试胚胎模式修复来自细胞间生化信号耦合和细胞间被动机械相互作用的中心假设。这一假设将通过整合机械建模、控制遗传操作和高维成像来推断或逆向工程，对沿头尾轴定义果蝇身体计划的多个表皮片段进行模式修复的逻辑进行验证。基于团队的本科研究经验和高中科学展览项目将促进统一的开源应用程序MAPPER的创建和测试，用于分析多路复用组织数据。通过与北印第安纳州研究科学与工程博览会（NIRSEF）委员会的合作，PI将组织年度“科学博览会新兵训练营”研讨会，作为印第安纳州南本德及周边地区代表性不足的高中生的新招聘途径。科学博览会训练营和科学博览会活动将作为少数民族学生的外展活动。一份新兵训练营手册将在NIRSEF网站上分发，作为全国可用的资源。

1553826Zartman, Jeremiah Uncovering how developing tissues are able to repair themselves is of fundamental importance for devising new strategies for treating birth defects or tissue degenerative diseases. The goal of this NSF CAREER proposal is to establish an interdisciplinary research-education-outreach program that rests on three legs: (i) quantitative, systems-level analysis of the mechanisms governing tissue growth and homeostasis; (ii) education of chemical engineers and bioengineers with a strong foundation in developmental biology and tissue engineering; and (iii) outreach in the local community to recruit students into science and engineering from underrepresented backgrounds. In particular, this project seeks to significantly expand our understanding of how embryos are able to correct early mistakes in specifying the relative spatial distributions of cell types during tissue formation. A deeper understanding of cell signaling and mechanics during pattern repair can inform applications in synthetic biology, including devising ways to manipulate cellular decision-making processes in space and time.The overall goal of this CAREER proposal is to build an integrated research-education-outreach program that develops and teaches systems biology approaches from an engineering perspective. In particular, this project seeks to significantly expand our understanding of how embryos are able to correct early mistakes in specifying the relative spatial distributions of cell types during tissue formation. Embryos exhibit a remarkable ability to repair patterning defects when subjected to environmental variation or genetic deficiencies. Identifying the control systems that repair tissues is important for understanding the underlying causes of birth defects as well as diseases that occur due to misregulated growth. This project will generate new imaging methods, open-source data analysis tools for multiplexed image data generated for a genetic model system of tissue pattern repair, the fruit fly (Drosophila melanogaster), and simulation resources widely applicable to studies on the maintenance of tissue microenvironments. The PI's team will test the central hypothesis that embryonic pattern repair emerges from the coupling of intercellular biochemical signaling to the passive mechanical interactions between cells. This hypothesis will be tested by integrating mechanistic modeling, controlled genetic manipulations, and high-dimensional imaging to infer, or reverse engineer, the logic of pattern repair for the multiple epidermal segments that define the fruit fly's body plan along the head-tail axis. Team-based undergraduate research experiences and high school science fair projects will facilitate the creation and testing of a unified open-source application called MAPPER for analyzing multiplexed tissue data. Through collaboration with the Northern Indiana Research Science and Engineering Fair (NIRSEF) Committee, the PI will organize annual 'Science Fair Boot Camp' workshops as a new recruitment avenue for underrepresented high school students in South Bend, IN and surrounding areas. The Science Fair Boot Camp and science fair activities will serve as outreach to minority students. A Boot Camp Handbook will be distributed on the NIRSEF website as a nationally available resource.