NSF/MCB-BSF: Quantitative analysis and modeling of Notch signaling using in vivo synthetic biology

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How an animal develops complex tissue types during its lifetime is an important and fundamental question. Many cell signals are required to work together so this process works flawlessly. This project will systematically build a theoretical understanding of a cell signaling pathway in developing fruit fly embryos. Like many genetic pathways required for animal development, this signaling pathway was initially discovered using fruit flies and later shown to be essential for normal human development and health. This project will foster scientific collaborations between the U.S and Israel. Students from biology, engineering, and physics will examine how an external signal is converted into specific outputs using experimental and computational approaches. Both graduate and undergraduate students will be trained by a multidisciplinary research team that has wide-ranging expertise in laboratory and theoretical methods. Undergraduate students in Biomedical and Computer engineering will gain hands-on laboratory experiences and work with advanced students as a team, to achieve a common goal. This will help them to communicate ideas and results to fellow students and will promote interdisciplinary training.The central aim of this collaborative research project is to understand how different cell types convert the same cell signaling pathway into distinct responses during animal development. Defining how a signal invokes appropriate cell responses is of fundamental importance because signaling pathways ensure essential cell types are generated throughout an organism's lifespan. The Notch signaling pathway in Drosophila is iteratively used to invoke distinct responses in different cell types throughout animal development. The specific goals of this project are to develop a systematic, quantitative understanding of how the Notch signal is converted into cell-specific outputs using an in vivo synthetic biology approach and mathematical modeling. Drosophila carrying a set of reporters that systematically vary in number and architecture of Notch-regulated DNA binding sites will be created. Quantitative expression analysis and transcription factor occupancy data will be obtained using high resolution imaging of fixed and live tissues. Experimental data will be used to build mathematical models and computational simulations. Models will be based on a statistical mechanics description of transcription to describe how key parameters (DNA binding sites, ratios of effector proteins, binding affinities, and protein degradation) alter Notch output. Predictions from these models will be tested experimentally and will be used to improve the mathematical models. A quantitative description for the core Notch transcription module will provide a framework to systematically explore the role of additional biological factors on Notch-mediated transcription.This collaborative US/Israel project is supported by the US National Science Foundation and the Israeli Binational Science Foundation.