CAREER:Integrative Analysis for Reverse Engineering Embryonic Pattern Repair Mechanisms

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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.