CAREER:Integrative Analysis for Reverse Engineering Embryonic Pattern Repair Mechanisms

发现发育中的组织如何能够自我修复，对于设计治疗出生缺陷或组织退行性疾病的新策略具有至关重要的意义。这份NSF职业计划的目标是建立一个跨学科的研究-教育-外展计划，该计划基于三个方面：(I)对组织生长和动态平衡的机制进行定量的、系统的分析；(Ii)对在发育生物学和组织工程方面具有坚实基础的化学工程师和生物工程师进行教育；以及(Iii)在当地社区进行外展，以招收来自代表性不足的背景的学生进入科学和工程专业。特别是，这个项目试图显著扩大我们对胚胎如何能够纠正早期错误的理解，即在组织形成过程中指定细胞类型的相对空间分布。对模式修复过程中细胞信号和力学的深入理解可以为合成生物学中的应用提供信息，包括设计在空间和时间上操纵细胞决策过程的方法。这项职业提案的总体目标是建立一个从工程角度开发和教授系统生物学方法的综合研究-教育-推广计划。特别是，这个项目试图显著扩大我们对胚胎如何能够纠正早期错误的理解，即在组织形成过程中指定细胞类型的相对空间分布。当受到环境变异或遗传缺陷的影响时，胚胎表现出非凡的修复图案缺陷的能力。确定修复组织的控制系统对于了解出生缺陷以及因生长调控不当而发生的疾病的根本原因非常重要。该项目将产生新的成像方法、为组织模式修复的遗传模型系统--果蝇产生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护研究的模拟资源。PI的团队将测试中心假设，即胚胎模式修复出现在细胞间生化信号与细胞之间被动机械相互作用的耦合中。这一假设将通过集成机械建模、受控遗传操作和高维成像来推断或反向工程多个表皮片段的模式修复逻辑来验证，这些表皮片段定义了果蝇沿着头尾轴的身体规划。基于团队的本科生研究经验和高中科学博览会项目将促进一个名为MAPPER的统一开源应用程序的创建和测试，以分析多路组织数据。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将组织一年一度的“科学博览会训练营”研讨会，作为南本德省、印第安纳州及周边地区代表不足的高中生的新招募途径。科学博览会训练营和科学博览会活动将作为对少数族裔学生的外展活动。一本训练营手册将作为全国可用的资源在NIRSEF网站上分发。

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.